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Endless Fascination∗

William E. Paul

Laboratory of Immunology, National Institute of Allergy and Infectious Diseases,National Institutes of Health, Bethesda, Maryland 20892-1892; email: [email protected]

Annu. Rev. Immunol. 2014. 32:1–24

First published online as a Review in Advance onOctober 23, 2013

The Annual Review of Immunology is online at immunol.annualreviews.org

This article’s doi:10.1146/annurev-immunol-032713-120247

∗ This is a work of the US Government and is not subject to copyright protection in the UnitedStates.

Keywords

cytokines, AIDS, antibody specificity, Th2 cells, major histocompatibilcomplex, immune response genes, interleukin-4

Abstract

Each of us fortunate enough to have had a career in experimental scihas a tale to tell, often one with surprising twists and turns, full of lesthat can help guide those embarking on a similar journey. At the very lea

well-written recounting of a career can be entertaining. I offer my mem version of my career in immunology and hope the readers will find it of v

or at least of interest.

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FurtherANNUAL

REVIEWS

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FIRST WORDS

As I assume is the case for anyone asked to write an Annual Reviews prefatory article, my first

reaction is, “It’s too early for that; I’m busy thinking about new experiments, not about summingup a lifetime in science.” Nonetheless, having accepted the editors’ generous invitation, I shall try

to say something that may interest at least a few of the devoted readers of the Annual Review of

Immunology, a publication to which I have given 31 years of effort (more about that later!).

CATCHING THE WAVE

I judge myself fortunate to have “caught the immunology wave.” The field was just revving up

when I entered it, and it has never looked back. I was taught that all branches of science go throughrelatively short periods of intense creativity, adding new concepts, followed by long periods of

consolidation. During the time I have been seriously involved in immunology—since 1964—Ihave yet to see a respite from the breakneck speed at which the field has expanded and created

new paradigms. Consolidation is long overdue, but I doubt my colleagues will give it a chance.I still recall my first attraction to immunology. Somehow, I came into possession of a slender

volume of essays by Michael Heidelberger, the father of quantitative immunochemistry, describingthe remarkable specificity of antibodies and his vision of the chemical forces underlying this

specificity. I recall that I started reading this on a trolley car in Brooklyn, during my college days,and I was smitten. As I describe below, I later had the good fortune to work at the New York

University School of Medicine in the lab next to Michael—as he was universally called in that

era. He and my postdoctoral mentor, Baruj Benacerraf, were the sponsors of my application formembership in the American Association of Immunologists (AAI).

EDUCATION AND CLINICAL TRAINING

But first a little history. I was born in Brooklyn, New York. My father came to the United Statesas a boy from a small town near Poltava, Ukraine, and my mother was born in New York City.

Her parents had come from Galicia, in the Polish portion of the Austro-Hungarian Empire.I was educated in public schools in New York City and did my undergraduate work at Brooklyn

College, where I received what I still regard as an outstanding education. In that era, New YorkCity provided a close-to-free college education through its four excellent undergraduate colleges:

City College, Hunter College, Brooklyn College, and Queens College. Like so many others, I amdeeply indebted to the city for its willingness to provide such an education for all its citizens.

After college, I went to medical school, still in Brooklyn, at the State University of New York College of Medicine. While by no means a research powerhouse, SUNY Downstate had

some outstanding faculty members. The electrophysiology group, led by Chandler Brooks and

Brian Hoffman, was outstanding. Both Brooks and Hoffman were later elected to the National Academy of Sciences. Jack Gross, a professor of anatomy, had codiscovered the thyroid hormone

triiodothyronine.

In my second year of medical school, when students typically took pharmacology, a new chair-man arrived from Oliver Lowry’s program at Washington University. Thirty years later, workingin a very small laboratory, Robert Furchgott went on to show that the blood vessel relaxing

principle—which he called endothelium-derived relaxing factor—was nitric oxide. He thus initi-ated the era of nitric oxide as a master signaling molecule, for which he received the Nobel Prize

in Physiology or Medicine in 1998. I had the good fortune to be a member of the Lasker Prize jury that awarded Furchgott its Basic Medical Research prize in 1996.

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I still recall, though, that our professor of microbiology at Downstate, who had been president

of the AAI, had great skepticism regarding the importance of lymphocytes in adaptive immunity. At the time, it seemed quite preposterous that these small cells, basically nuclei with the barest

rim of cytoplasm, could have a central role in determining the specificity and effector functions of immunity.

My first experience with research came in the summers after my first and second years of medical school when George Talbert, a quite wonderful but subdued man, gave me a place in his

lab, where I studied the production of growth hormone in the pituitary of pre- and postnatal rats. This was an interesting beginning in science and also served to make me an attractive candidate

for my first research/clinical appointment at the National Institutes of Health (NIH).I had met the love of my life, Marilyn Heller, in the summer before my senior year in college,

and we were married midway through my third year of medical school. Marilyn and I spent the

following summer in the DC area, where I had my first experience at NIH doing some not very exciting epidemiologic research in what was then the National Institute of Neurologic Diseases

and Blindness. But that summer introduced me to the Bethesda institution that has been my scientific home for all but a few years of my professional life, and it allowed the two of us to feel

the attraction of the nation’s capital. After I graduated from medical school, Marilyn and I moved to Boston, where I was an in-

tern and then an assistant resident in medicine at the Massachusetts Memorial Hospitals (now Boston Medical Center). During my assistant residency, I worked in Alan Cohen’s laboratory at

Mass Memorial (Figure 1). Alan was an electron microscopist and a leading figure in the study of amyloidosis. Using immunoelectron microscopy, then a new and exciting technology, we charac-

terized some of the structural components of amyloid fibrils, a study that led to papers in Nature

(1) and the American Journal of Pathology (2), my first publications.

RESEARCH AND PATIENT CARE AS A CLINICAL ASSOCIATE AT NIH

I had the good fortune to obtain a clinical/research position at NIH, allowing me to fulfill my

military responsibility as a commissioned officer in the United States Public Health Service. Ihad been selected by a group whose research interests were in protein and steroid hormones and

had been chosen by Roy Hertz, the chief of the Endocrinology Branch of the National CancerInstitute (NCI), to be his postdoc, no doubt based in part on my work on rat pituitary hormones

with George Talbert and George’s generous recommendation. When I joined the Endocrinology Branch of NCI, in July 1962, Hertz and his colleague

M.C. Li had already shown that metastatic choriocarcinoma could be cured by treatment withmethotrexate (3). This was a remarkable discovery, the first instance when a metastatic cancer was

cured with drugs. As a clinical associate in this group, I had the privilege of caring for the young

women who had come to NIH for treatment. In that era, virtually every woman in the UnitedStates who had developed “chorio” came to Bethesda to be treated, and 70% of them went home

cured. One can hardly imagine a more exciting clinical experience.

The first year of my NCI appointment was theoretically a full-time clinical year, but we hadnights and weekends to do research, and although I was formally Roy Hertz’s postdoc, I actually worked with two other members of that branch, Bill Odell and Griff Ross. With Odell and another

clinical associate, Jack Wilber, we developed the first radioimmunoassay for thyroid-stimulatinghormone (4). I also carried out an extensive series of studies on the immunological/biophysical

properties of chorionic gonadotropin, human pituitary gonadotropins, and adrenocorticotropichormone (5–7).

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Figure 1In Alan Cohen’s laboratory at Mass Memorial in 1962; I am in the middle of the back row.

NIH was a remarkable place in that era. Because one could do one’s military service as a researchor clinical associate, NIH positions were extremely sought after, resulting in a remarkably talented

group of young physician-scientists who were brought together under one roof (well, not exactly“one” roof). Mike Brown and Joe Goldstein have described this golden era in a recent article in

Science (8), pointing out that of the NIH postdocs in the period from 1964 to 1972, nine went onto become Nobel laureates. The number almost certainly would have been ten if Charlie Janeway

a postdoctoral fellow in my lab beginning in 1970, had not died prematurely.Despite two outstanding years in Bethesda, I did not believe I was getting the necessary training

for a truly productive career in science. Furthermore, I had already decided while I was still inBoston that I wanted to do immunology research,not endocrinology. Given my changing interestsbeforeI leftMass Memorial for NIH, Alan Cohen sent me to see two Boston immunologists, Byron

Waksman, then at Massachusetts General Hospital, and Sidney Leskowitz, at Tufts UniversitySchool of Medicine. Byron and Sid agreed that the two most exciting places to do postdoctoral

research in immunology were the labs of Henry Kunkel at the Rockefeller University and of BarujBenacerraf at the NYU School of Medicine.

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Based on that advice, I applied to both Kunkel and Benacerraf. Henry explained that his lab

was full, although he might be willing to take me on as a PhD student. By then, Marilyn and I hadour first son, Jonathan, and I found the idea of beginning an open-ended PhD just too daunting. I

had visited Henry’s laboratory on a Friday in October 1962 and came to see Baruj on the following Monday. The weekend between was the culmination of the Cuban Missile Crisis, so the trip to

New York remains deeply etched in my memory.Baruj’s laboratory was located on the fifth floor of the NYU Medical Science Building, which

recently suffered enormous damage in Hurricane Sandy. I still clearly recall that 1962 visit. Baruj was seated at a bench in his double module wearing his signature brown lab coat. Hanging from a

pipe below the ceiling was a certificate attesting to his receipt of the gold medal of the Reticuloen-dothelial Society for his pioneering work quantifying the phagocytic behavior of macrophages in

vivo. Baruj sent me to see his colleagues in the Pathology Department at NYU, including Jeanette

Thorbecke and Zoltan Ovary. He described his own research program, asked me some questionsabout what I had done and what I wanted to do, and then sent me on my way home. Two weeks

later, Baruj sent me a letter indicating that I could come to his lab but that he intended to takea sabbatical at about the time I would arrive. Because the letter did not clarify whether he was

accepting me to work with him or with one of his colleagues, I screwed up my courage and askedhim if he meant that I could work directly with him (he was as formidable a personality then as

he was in his days as president of the Dana-Farber Cancer Institute and as Fabyan Professor of Pathology at Harvard). The word arrived that I could work directly with him, so Marilyn and I

resolved that when the two-year stint at NIH ended, we would return to New York City, this timeto Manhattan, and I would join the Benacerraf “family.” Although Baruj always threatened to take

a sabbatical, he never actually did.

NYU DAYS

On July 1, 1964, I appeared at room 527 of the NYU Medical Science Building ready and eager

to start working, only to discover that everyone was either away on vacation or about to leave. As was his practice, Baruj was in Paris for a month, and Carmen Merryman, a postdoc who came to

be a good friend, was going cruising. Carmen greeted me as she was going out the door with theinjunction that I was to “bleed my rabbits!”

The only person in the lab during those summer months in 1964 was Ira Green, who hadarrived in Baruj’s lab two weeks before me. We would remain colleagues and close friends until his

death in 2011. Although we had what we thought were different projects (eventually we realizedhow similar they were), we helped one another and were coauthors on virtually all our papers

(Figure 2).NYU was a true international center of immunology at that time. Among the faculty in

addition to Benacerraf, Thorbecke, and Ovary were Michael Heidelberger, Jonathan Uhr,

Edward Franklin, Chandler Stetson, Lewis Thomas, Kurt Hirschhorn, Jerry Lawrence, Robert McCluskey, Victor and Ruth Nussenzweig, Michael Lamm, and Gregory Siskind. Benacer-

raf was the intellectual leader, but he actually had a very small lab. During my four years

there, the number of postdocs who came through could not have been more than eight.But with those eight, much was accomplished! As Ron Germain and I have written in arecent pr´ ecis of Baruj’s career (9), these were the culmination of the Benacerraf wunderjahre

(Figure 3). He had come to NYU from Paris in 1956 and had quickly made critical breakthroughsin understanding the specialization of distinct classes of immunoglobulins and the specificity

of cellular immune responses. He had discovered Fc receptors and immune response ( Ir )genes.


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Figure 2

Baruj Benacerraf and Ira Green at NYU in 1964.

While I was in the Benacerraf lab, Arthur Berken completed the description of Fc receptors.

Even more importantly, Baruj discovered Ir genes with Bernard Levine, studying immune re-sponses to hapten-poly-L-lysine conjugates in guinea pigs. How Ir genes mediated their function

was the project assigned to Ira Green. That analysis was carried largely to completion during our

Figure 3

With Baruj and Annette Benacerraf.

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years at NYU and in Baruj’s two successive years in Bethesda. For this work, Baruj received the

Nobel Prize in 1980. My research program in Baruj’s laboratory was to work out the specificity of cellular immune

responses and compare that with the specificity of antibodies that were nominally directed to thesame antigen. B and T cells had not yet been distinguished, but we knew that antibody and cellular

immunity were different, and skin testing had indicated that cellular immunity to a hapten-carrierconjugate displayed carrier specificity, whereas anti-hapten antibody apparently did not. My job

was to develop a simple and reliable in vitro assay that could quantitatively examine the specificity of cellular immune responses in a hapten-carrier system and, in parallel, to use physical methods

to precisely determine the contribution of carrier to the energy of binding of an anti-haptenantibody. Wonder of wonders, both succeeded.

I had read anelegant paper byDickDutton(10)written while he was still in Londonthatshowed

that spleen cell suspensions from immunized rabbits would take up 3H-thymidine when stimulatedin vitro with the immunogen but not with unrelated antigens. That provided the necessary tool

and allowed me to study in detail the requirements for in vitro responses of guinea pig lymphnode lymphocytes from donors immunized with given hapten-carrier conjugates using the same

hapten conjugated to many different proteins and the same carrier with many alternative haptenconjugates. We could show clearly that there was little or no cross-reactivity if the carrier was

changed, and we could examine the degree of cross-reactivity as the hapten was altered. Indeed,I found that the requirements for homology between the carrier used for immunization and that

used to elicit a response was almost complete. If the carriers were unrelated proteins or amino acidcopolymers, virtually no concentration of that hapten-carrier conjugate would elicit 3H-thymidine

uptake on the part of lymphocytes from immunized donors. There was a degree of cross-reactivity

if we used various nitrophenyl hapten conjugates of the carrier used for immunization to stimulatelymphocytes from donors primed with a 2,4-dinitrophenyl protein (11).

When I turned to an analysis of binding affinity of purified anti-hapten antibodies, I was able toshow a contribution of the carrier to the free energy of binding, but the contribution was relatively

modest. We used spectrophotofluorometry to measure the quenching of antibody fluorescencethat occurs when the absorption frequency of the ligand overlaps the emission frequency of tryp-

tophans in the antibody. We estimated that ∼10% of the free energy of binding of an anti-DNPantibody to the DNP-carrier conjugate used for its elicitation could be attributed to the structure

of the carrier molecule, whereas when the antibodies elicited with a distinct DNP-carrier complex were tested, their energy of binding to the test ligand was less than that to ε-DNP-L-lysine (12).

This work unequivocally demonstrated that the specificity of cellular immune responses (today, we would say T cell responses) and antibody (and presumably B cells) was strikingly different.

Although working with Baruj and the postdocs in his lab—including Ira Green, Arthur Berken,Carmen Merryman, Jean-Pierre Lamelin, John F ¨ oerster, Herb Oettgen, and Takeshi Yoshida—

was a remarkable experience, the end was not what I would have wished. Basically I and, more

importantly, Baruj were, in effect, forced out of NYU.I had been trained in medicine and, at that time, still saw myself as a physician-scientist.

Indeed, I eventually was elected president of the American Society for Clinical Investigation

(ASCI), perhaps the leading general clinical research association. Although I was happy working with Baruj in the NYU Pathology Department, I hoped for an opportunity in the Department of Medicine. This seemed likely given that Lewis Thomas was chair of medicine and he and Baruj

arranged for me to become an instructor in medicine in what would prove to be my last year at NYU (1967/1968). I had received no guarantees about the future, but others had trod that path

successfully toward more senior appointments. However, in the spring of 1967, Thomas becamedean of the School of Medicine and a new chair of medicine was appointed. I was summoned to


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his office and was stunned to be told that he could not “see a single reason to appoint me as an

instructor in medicine,” despite my considerable medical training and by then quite substantialresearch record. I recounted this to Baruj, and through the combined efforts of him and Thomas,

the appointment as an instructor did come through; I could have no illusions of a future at NYUhowever. I began looking for opportunities elsewhere.

Shortly, even Baruj found that NYU was not an institution to count on for the developmentof his own burgeoning career. Baruj had been asked by Thomas to consider becoming the chair

of anatomy at NYU, a position that had been vacant for an extended time. Baruj was interestedbut wanted to see the department modernized and proposed that it be retitled as cell biology. The

search committee met and decided not to offer Baruj the chair of anatomy/cell biology. Rather,a proposal was made to create a division of immunology that consisted of the relatively modest

amount of space that he had already been assigned. Rather astonished, Baruj resolved to leave

NYU. Fortunately, the position of chief of the NIAID Laboratory of Immunology (LI) becameopen and was offered to Baruj. He was attracted to the LI not only because of the scope it would

give him to develop a much more integrated research program, but also because his work on Ir

genes had been conducted with outbred guinea pigs. NIH was the one place in the world where

major colonies of inbred guinea pigs existed, and as LI lab chief he would have excellent access tothese useful animals.

Baruj accepted the offer and, to my pleasure, invited me and Ira Green to join him in BethesdaSo our family, now increased by Matthew’s birth in New York City, returned to Bethesda in July

1968, and I took up what proved to be permanent residence on the eleventh floor of Building10.

RETURN TO NIH

We quickly settled into our new labs and were hard at work with almost no time lost. Marilynand I and our boys had just returned from eight weeks in London, where I had a mini-fellowship

with Avrion Mitchison at the National Institute for Medical Research in Mill Hill. Av had doneand was extending a brilliant series of experiments in which he showed that the carrier specificity

of secondary anti-hapten antibody responses to hapten-carrier conjugates could be accounted forby a cell with carrier specificity and a distinct cell that was hapten specific (13). Not surprisingly,

the carrier-specific cell proved to be the T cell, consistent with my work showing that cellularimmunity was intensely carrier specific, and the hapten-specific cell was the B cell, also in accord

with the small contribution the carrier made to hapten-specific antibody binding. I proposedto Baruj that we use this finding as a take-off point for a new series of experiments aimed at

understanding the dynamics of cell cooperation in primary and secondary antibody and cellularimmune responses in hapten-carrier systems. David Katz and Edmond Goidl joined us in this

work, which proved very successful (14, 15).

In addition to my collaboration with Baruj, to which we had agreed I would allot half my time,I undertook an independent series of experiments on the binding of antigen to specific B cells

(16), working with an exceptionally talented postdoc, Joseph Davie, who went on to be chair of

microbiology at Washington University School of Medicine and then to a successful career in thebiotech industry.

But while research was progressing well, new changes were afoot. Shortly after Baruj’s move to

Bethesda, he was approached by the leadership of Harvard Medical School to gauge his interest inits chair of pathology, and by the spring of 1969, he had decided to accept the position, although

he did not leave NIH until June 1970. This obviously changed everything and made me rethinkmy situation. Baruj asked me to move to Harvard with him, but I was reluctant to do so, believing

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that making more than one move with a former mentor was an announcement of dependence. We

were told that Robert Schwartz, an eminent hematologist/immunologist from Tufts, would takeover the leadership of the LI, and although I thought he would make a good lab chief, I began

looking for other opportunities and received quite nice offers. But a few months before he was toarrive came the announcement that Schwartz had decided against taking the position.

John Seal, the scientific director of NIAID, who was the top official in the institute’s intramuralresearch program, then decided to look within NIH for Baruj’s replacement. There were excellent

candidates more senior than either Ira or I. However, Ira declared that he did not want to be labchief and that I should try for the position (an act of generosity for which I have always been

grateful). Baruj threw his influence behind my candidacy, and in due course I was offered the job.In July 1970, at age 34, I became the youngest lab chief on the NIH campus and moved into

the office that Baruj had occupied, room 11N311 in the NIH Clinical Center, which remains my

office to this day.

LABORATORY CHIEF

The LI I inherited from Baruj was a work in progress. The lab had been founded in 1957 asthe first immunology research center in the NIAID intramural research program. It was headed

initially by Jules Freund, a leader in the study of immunologic adjuvants, for which he had receivedthe Albert Lasker Basic Medical Research Prize. Freund died in 1960, ironically from multiple

myeloma. He was succeeded by Maurice Landy, an expert in endotoxin. The Landy years werenot good ones at the LI, and with the exception of the rabbit immunogenetics program headed by

Sheldon Dray and the group of Ralph Reisfeld, the lab was in disarray. With the announcement of

Baruj’s appointment, several members of the lab left (such was the power of his name) and others were reassigned. Indeed, some of the best left, notably Dray and Reisfeld. But others remained,

including Rose Mage and John Inman, as did Rose Lieberman, whom Baruj had recruited fromanother NIAID lab. They were excellent colleagues, but the LI had been depopulated. I thus had

the job of rebuilding while still establishing myself as a serious senior scientist. Over several years,the lab was rebuilt and became a center of excellence.

THE FIRST POSTDOC ONSLAUGHT

We were fortunate to have superb postdocs, which enabled us to move carefully with the process

of recruiting new senior staff. The list of those who came to the LI as postdocs in the initial yearsafter I became lab chief was quite exceptional. It includes Joe Davie, David Katz, Charlie Janeway,

Jack Stobo, Ethan Shevach, Zami Ben-Sasson, Don Mosier, Ben Schwartz, Ron Schwartz, FredFinkelman, Kim Bottomly, Michael Harrison, Jimmie Mond, Michael Gelfand, Constantin Bona,

and David Thomas. Alan Rosenthal and Irwin Scher, although not postdocs, were close collabo-

rators. I was lulled into the false sense that being a principal investigator (PI) was a simple task. PIs“planted the seed” of a good project (Baruj’s term) and watched extraordinarily talented postdocs

make the experiments “bloom.”

GREAT POSTDOCS REDUX

After a respectful interval, the LI welcomed a second group of outstanding fellows including Mark Davis, Laurie Glimcher, Maureen Howard, Tony DeFranco, Steve Hedrick, Wayne Yokoyama,

John Kung, Larry Samelson, Jon Ashwell, Dan Longo, Lou Matis, Drew Pardoll, Ellen Heber-Katz, Kenji Nakanishi, Takashi Saito, Junichi Ohara, Melissa Brown, and Reinhard Burger. To


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build our senior staff, Ethan Shevach and Ron Schwartz were appointed from within the lab. In

1982, we recruited Ron Germain, who had worked with Baruj at Harvard, and in 1983 David Margulies, who had been a postdoc with Phil Leder and Jon Seidman in NICHD. Thus, by

1983, we had an outstanding list of mostly young PIs consisting of myself, Ira Green, EthanShevach, Ron Schwartz, Ron Germain, Rose Lieberman, David Margulies, Rose Mage, and John

Inman.

A FEW LI HIGHLIGHTS

Ir Genes, MHC, and Restriction

Assembling our PI staff gave us the critical mass for some outstanding accomplishments. The firstand one of the most important was work by Ethan Shevach, first with Ira Green and me and later

with Alan Rosenthal, a colleague in the NIAID Laboratory of Clinical Investigation. Ira’s andBaruj’s work on Ir genes had shown that they controlled the capacity of simple carrier molecules

such as mono- or di-amino acid polymers, to elicit immune responses to any hapten conjugate of

those carriers, even though these responses were often not cross-reactive. In particular, strain 2guinea pigs were capable of responding to the copolymer of glutamic acid and lysine (GL) and

its hapten conjugates but not to the copolymer of glutamic acid and tyrosine (GT) or any of itshapten conjugates. Strain 13 guinea pigs had the opposite responsiveness pattern and (2 × 13)

F1 guinea pigs responded to both sets of antigens. When Ethan Shevach joined Ira’s lab, theyprepared antibodies in strain 2 guinea pigs against strain 13 lymphocytes and vice versa. These

alloantisera principally recognized guinea pig MHC class II molecules. Together, we undertook an experiment to examine the capacity of these antisera to inhibit

the in vitro 3H-thymidine uptake responses of T lymphocytes from F1 guinea pigs immunized with both DNP-GL and GT in complete Freund’s adjuvant, responses that depended on antigen-

presenting cells (APCs) also derived from F1 donors. The experiments were unequivocal. Theanti–strain 2 antibody completely blocked the response of the F1 cells to DNP-GL, to which strain

2 guinea pigs were responders, but had no effect on the response of the same cell population toGT, to which strain 13 guinea pigs were responders. The anti–strain 13 sera completely inhibited

the response to GT but had no effect on the response to DNP-GL. These results were published

in the Journal of Experimental Medicine in 1972 (17) and were quickly followed by experimentsthat Shevach and Rosenthal carried out, also published in that journal in 1973, in which they

showed that responsiveness of F1 cells to DNP-GL could be elicited by APCs from strain 2 butnot strain 13 donors, whereas the response to GT required strain 13 APCs; no response was

obtained with strain 2 APCs (18, 19). These experiments indicated that MHC class II moleculesplay a critical role in the presentation of antigens by APCs to T cells and that polymorphisms in

class II determined the specificity of such control. This result implied that T cell recognition was MHC-restricted and that Ir genes were MHC class II molecules. They foretold the specificity of

the T cell receptor (TCR) for peptide/MHC complexes.By 1976, Ron Schwartz and I had repeated and extended these key experiments in the mouse,

validating the conclusions in a setting in which both the genetics and the specificity of the antibodies

were clear (20). These results thus established the MHC restriction of CD4 T cell antigen recog-nition and mapped Ir gene function to such recognition. Laurie Glimcher prepared MHC class II

point mutants and showed that they altered antigen-presenting function (21). Ron Schwartz inde-pendently also provided compelling evidence that Ir gene products were MHC class II molecules

and then, with his postdoctoral fellows Marc Jenkins and Helen Quill, discovered clonal anergyand worked out its mechanistic basis.

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mIg Is a Receptor, and the Definition of Type I and Type II Thymus-Independent Antigens

At about the same time, John van Boxel, Ira Green, William Terry, and I were the first to show that B cells express membrane IgD as well as membrane IgM (22). With Donna Sieckmann, Richard

Asofsky, and Donald Mosier, we provided strong evidence that membrane immunoglobulin (mIg)functioned as a true receptor (23, 24). That had been a highly controversial subject. Others had

argued that ligands for mIg served only to concentrate antigenic complexes on the B cell surface,

whereas other structures such as lipopolysaccharide, as part of these complexes, actually stimulatedthe responses. Today, it is of course clear that mIg is the B cell’s receptor, but it is also true that

complexes of antigens and Toll-like receptor ligands have particularly potent stimulatory activity. With Rafi Sharon and Phil McMaster, we introduced the use of hapten-Ficoll conjugates as im-

munogens (25), and based on studies of responses to various antigens, Mosier and I proposed that antigens be divided into three general groups, thymus-dependent antigens, thymus-independent

type I (intrinsic stimulants such as trinitrophenyl-lipopolysaccharide) antigens, and thymus-independent type II (hapten conjugates of repeating structures such as hapten-polysaccharides)

antigens.

BCGF, BSF-1, AND IL-4

I don’t wish to clutter this article with research descriptions, so I leave unsaid much of the other

work going on at the same time. However, the early 1980s produced two accomplishments at theLI that must be mentioned. The first represents work done in my group deriving from our earlier

demonstration that mIg was an actual receptor (i.e., a signal-transducing molecule). Indeed, Tony DeFranco showed that engaging mIg with goat anti-mouse IgM caused tyrosine phosphorylation

of a series of substrates, and he traced its induction of B cell activation to a commitment point in lateG1, where the B cells would then complete the cell cycle even when the stimulant was withdrawn

(26). When Maureen Howard showed that the proliferative response of B cells to anti-mouse IgM

was very cell density dependent, we speculated that it might be due to the presence of another cellthat was producing a factor necessary for, or contributory to, anti-IgM-driven B cell proliferation.

Maureen and I showed that the supernatant of an EL-4 cell line contained a factor that allowed

B cells cultured at low density to proliferate in response to anti-IgM. Maureen then demonstratedthat this was not IL-2, as had been speculated, but was a previously unrecognized molecule that wepartially purified and designated B cell growth factor (BCGF) (27). Later, Junichi Ohara purified it

to homogeneity (28). BCGF morphed into B cell stimulatory factor-1 (BSF-1) and, after its cloningand purification, became IL-4. Ellen Vitetta and Peter Krammer and their colleagues reported a

factor that caused switching to IgG1 in the same 1982 issue of the Journal of Experimental Medicine

(29) in which Maureen and I had reported the discovery of BCGF. Subsequently, Ellen’s lab

and mine collaborated to show that IL-4 was the IgG1-switch factor (30), and simultaneously we

collaborated with Bob Coffman to show that IL-4 was the IgE-switch factor (31).

TCR β Chain Cloning While we were hard at work on IL-4, I was surprised and delighted that Mark Davis chose to dohis postdoctoral work in my research group. Mark had completed a remarkable PhD with Lee

Hood at Caltech, where he had worked out the molecular biology of immunoglobulin heavy chain V(D)J recombination and of class switching. In my group, he undertook a study of differences

in expression of mRNAs between B and T cells, using RNA hybridization kinetics and cDNA subtraction to do the analysis. He concluded that these two lymphocyte types differed in ∼2% of


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their expressed genes (32). When he finished his two years under my mentorship, he had devised

a logical and creative plan to clone the TCR. The LI senior staff were enormously impressed,and we established Mark as an unofficial independent investigator to undertake this effort. Steve

Hedrick from Ron Schwartz’s group and David Cohen from mine, together with Ellen Nielsen, atechnician, joinedMark in a singleNIHmodule. In a remarkable 11-month effort, they successfully

cloned the β chain of the mouse TCR. Mark and his nascent group utilized subtraction of cDNAlibraries derived from mRNAs associated with membrane-bound polysomes of T and B cells to

enrich for T cell–specific messages for membrane and secreted proteins. They then screened thecDNAs they had obtained for evidence of rearrangement. The single clone that emerged encoded

the TCR β chain. The two Nature papers that described this work were authored by HedrickCohen, Nielsen, and Davis (33, 34); no LI PI was a coauthor. This remarkable accomplishment

fully justified the confidence that my colleagues and I at the LI had in Mark. We tried to persuade

him to stay at the LI, but the call of Stanford proved too strong.

A Few More Examples

Regulation of Ig class switching. My group continued its interest in IL-4. Cliff Snapper carriedout a remarkable series of experiments on the biology of cytokine regulation of class switching. He

showed that IFN- γ controlled switching to IgG2a and that IL-4 and IFN- γ competed with oneanother to establish the pattern of switching. The Science paper describing this work has received

more citations than any other paper of which I have been an author (35). My former postdoctoralfellow Fred Finkelman, then in his own laboratory, collaborated with us to show that IL-4 was

essential to in vivo production of IgE (36).

Mast cells and basophils produce cytokines. MelissaBrownhad shown that virally transformed

mast cell lines produced IL-4, IL-13, IL-5, and IL-3 when stimulated with PMA (phorbol 12-myristate 13-acetate) and ionomycin (37). When Marshall Plaut joined us to do a sabbatical, he

immediately tested the capacity of IL-3-stimulated mast cell lines to produce IL-4 in response tocross-linkage of FcεRI. The results were strikingly positive, initiating the continuing interest in

cytokine production by mast cells (38). With Bob Seder, we showed that basophils were an evenricher source of IL-4 than mast cells (39). We recognized the potentially crucial role of cytokine

production by mast cells and basophils in allergic inflammatory diseases.

Cytokines regulate Th1/Th2 polarization of CD4 T cells. We knew that IL-4 was made bysome T cell lines, and Bob Coffman and Tim Mosmann had shown that their long-term CD4 T

cell lines could be subdivided based on their pattern of cytokine production into Th1 and Th2

cells, the signature of the latter being IL-4 production. This inevitably led to the question ofhow the cells acquired these distinctive cytokine-production patterns. Graham LeGros and Zami

Ben-Sasson answered that question with a beautiful study in which they showed that naive CD4 T cells stimulated with anti-CD3 and anti-CD28 would develop into IL-4-producing cells only

if they were also cultured with IL-4 itself and IL-2 (40). Susan Swain did a similar experiment at

about the same time (41). To be sure of the physiological significance of this result, Bob Sederand I collaborated with Barbara Fazekas and Mark Davis to show that TCR transgenic cellsspecific for pigeon cytochrome c would differentiate into Th2 cells if stimulated with dendritic

cells, cytochrome c peptide, and IL-4 and IL-2 (42), clearly showing the central role of cytokinefeedback in T cell differentiation. Ken Murphy and Anne O’Garra did a similar experiment at

the same time (43). Indeed, in collaboration with Alan Sher, Bob Seder also used the in vitropriming model to show the importance of IL-12 in Th1 differentiation (44), which had also been

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demonstrated by Ken Murphy and Anne O’Garra (45). This in vitro priming model continues

to be a powerful tool to understand the roles of APCs and antigen dose and to explore how cytokines influence T helper cell subsets. Cytokine feedback has proven to be a general feature of

Th differentiation (46). As an aside, in the course of our review of the functions of IL-4, Bob Seder and I pointed out

that the effects of cytokines such as IL-4 were best understood in the context of their secretioninto the limited space created by the apposition of the T cell with its interacting cell, generally

a B cell, a dendritic cell, or a macrophage, and we suggested that this could be achieved by theformation of an immunological synapse between the interacting cell types owing to the recognition

of peptide/MHC by the TCR (47). This proposal has been cited as the inspiration for the modernstudy of the immunological synapse (48).

SOCIETIES AND PUBLICATIONS

The American Society of Clinical Investigation and the American Association of Immunologists

One of the great advantages of being an NIH scientist is that one need not write applications for

research grants, a process that I know is daunting and time-consuming. I thus had some compara-tively “free” time, which I have filled by undertaking editorial and organizational responsibilities.

I had been elected to ASCI in the 1972 and was later elected to its council and, in 1980, as itspresident. Then, as now, ASCI had to grapple with how to ensure that a cadre of talented clinical

investigators would be trained and supported. We did our utmost to lessen the training burden so

that individuals could become independent as early as possible in their careers. Indeed, I addressedthat point at length in my ASCI Presidential Address (49). This problem has not gone away and,

if anything, is far more severe in the current complex climate of health care delivery and waningsupport of clinical research.

I have been an involved member of the AAI since my election when I was a postdoc. I served asprogram chair and introduced the block system and the practice of having symposia in the morning

and posters and short presentations in the afternoon. Our goal was to organize the experience of meeting attendees so as to take advantage of the best features of small and large meetings.

I was elected to the AAI Council in 1981 and served as president in 1986–1987. A key problem we faced during those years was to ensure the viability of the Journal of Immunology (JI) and to

establish principles to govern the relationship of the AAI and the JI. At the time, as now, the JI was an international journal that drew submissions from the world immunological community.

It seemed essential that its financial position be secure, so we developed the principle that the JI

build a reserve equivalent to approximately one year’s expenses. If journal revenues exceeded what was needed to meet immediate needs and to build the reserve, the surplus would be used to lower

the cost of subscriptions or page charges, or both. The additional point was that the AAI shouldnot draw income from the JI beyond that needed to cover the costs it incurred on behalf of the

journal. The expenses of fulfilling the AAI’s functions should be met by dues and income from the

annual meeting. This established a healthy relationship between the AAI and the JI and ensuredthat both organizations flourished.

One major issue that was not successfully resolved was how the AAI dealt with clinical im-

munology. AAI had a Clinical Immunology Committee that had not played an active role whenthe field was growing rapidly. John Fahey and others had pushed for the establishment of an

independent entity, the Clinical Immunology Society (CIS), to meet the needs of the scientific(but also the practice) community in this field. We in the AAI leadership had hoped that scientists’


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needs in these areas could be met under the aegis of AAI and indeed worked toward that end.

While much was accomplished to strengthen the representation of clinical immunology in the AAI and at the annual meeting, the CIS was inaugurated and has played an important role in

shepherding the growth and meeting the needs of this field.

Fundamental Immunology and the Annual Review of Immunology

In 1980, Ann Paterson, an editor at Raven Press, a small scientific publisher based in New YorkCity, approached me about writing a medical student immunology text. I demurred, arguing that I

wasn’t a good choice because I had no role in teaching immunology to medical students. HoweverI did see a need for an authoritative text that covered the broad field of immunology. No such

book existed, andthus graduate students, postdocs, andsenior scientistsin immunology andrelated

areas had no single source to consult to ascertain the state of the field. I suggested that rather thanpreparing a text for medical students, we do a multi-author comprehensive textbook that would

cover the entire range of modern immunology. Ann brought the proposal to her colleagues atRaven Press, and Alan Edelson, its president, greeted the idea enthusiastically. Thus, Fundamental

Immunology was born. The first edition appeared in 1982 (50); it was about 800 pages long and cost about $.01 per

page. The seventh edition appeared in 2012 and is substantially longer and more expensive (51),but the organizing idea has remained the same. The goal has been to cover the major fields of

immunology, asking experts in these areas to write the chapters. The book begins with a generalintroduction to immunology, which I have written, followed by chapters dealing with the central

aspects of the immune system, then followed by chapters concerned with the various immune

regulatory and effector mechanisms and with the many areas where the immune system protectsagainst infection and tumors and where it contributes to or causes disease.

Fundamental Immunology has played an important role in training several generations of im-munologists, and I hope that it will continue to do so, though I recognize the changing nature of

information accessibility in this connected age. Interestingly, Fundamental Immunology’s publica-tion history seems to have followed that of the publishing industry in general. Raven Press was

purchased by the large Dutch publisher Wolters-Kluwer in 1987 so that, after three editions ofthe book under the Raven name, Lippincott-Raven served for the fourth edition (Lippincott was

also owned by Wolters-Kluwer). The fifth, sixth, and seventh editions have been published by yetanother merged entity, Lippincott Williams & Wilkins. What will the future bring?

While I was working on Fundamental Immunology, I was invited to attend a meeting at Asilomarduring the 1982 Midwinter Conference of Immunologists, to discuss the need for a review journal

in immunology. The leadership of Annual Reviews was interested in bringing out an immunology

review and wanted to gauge the enthusiasm of the immunological community for such a publica-tion. Winslow Briggs, the editor of the Annual Review of Plant Physiology, chaired the session that

was attended by a virtual Who’s Who of immunologists. In the end, there was great enthusiasmfor launching the Annual Review of Immunology (ARI), and the group asked me to act as editor and

Henry Metzger and Garry Fathman to be associate editors.

I was somewhat concerned about taking on this responsibility because I was still deeply involved with the first edition of Fundamental Immunology, but I bit the bullet and have been delighted thatI did so. Most of the attendees at the founding conference agreed to write reviews for Volume

1 of ARI (52), which ensured its success. ARI has been enormously popular and has published aseries of absolutely outstanding reviews throughout the years. Although impact factors have their

limitations, when judged by that metric or any of the other metrics that have been introduced, ARI had done spectacularly. During my 30-year tenure as editor, ARI was fifth or better of all

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publications in terms of impact factor, and for 7 years in a row it was first. Clearly, this has

represented an effort by a wide range of people, including an editorial committee, composed of theleaders in our field whoserve 5-year terms, andauthors, whohave invariably given us absolutely

first-rate manuscripts. It has also benefitted from a dedicated, able, and successful staff at AnnualReviews.

ARI’s goal is to get outstanding reviews to the immunological community in a timely manner,and it has eminently fulfilled this agenda. In 2012, Annual Reviews concluded it was time for a new

generation to take over leadership of ARI. Dan Littman and Wayne Yokoyama are now coeditors,so the journal is in the best of hands.

WORK WITH OUTSIDE ORGANIZATIONS

Most scientists are asked to aid in the work of outside organizations. I am fortunate to have had

several such opportunities. I limit myself to describing two: the Howard Hughes Medical Institute(HHMI) and the Lupus Research Institute (LRI). Today, HHMI has enormous impact on modern

biomedical science, but it was once a very modest organization, based in Coconut Grove, Florida,

and overseen by some of Howard Hughes’s former associates. In the late 1970s, George Thornand George Cahill of Harvard Medical School provided scientific leadership, but the process

of vetting HHMI scientists and choosing new ones was very idiosyncratic, largely because of thedirect involvement of Hughes’s associates, who had no scientific background. At that time, I served

with Henry Kunkel and Herman Eisen as one of the three HHMI advisors in immunology. When the courts held that the resources potentially available to HHMI based on its owner-

ship of Hughes Aircraft were far greater than it was devoting to research, revolutionary changesoccurred that propelled HHMI to the status it has today. I had the good fortune to continue to

serve HHMI in various ways during this transition period as a member of its Scientific Review Board and then of its Medical Advisory Board.

On a much smaller scale, LRI has also had a major impact in its field. Formed by members of the families of patients with systemic lupus erythematosus, the LRI has had the goal of supporting

innovative research to find new treatments that can halt progression as well as to strike at the root

causes of the disease. I have been chair of the Scientific Advisory Board of LRI since its inceptionmore than a decade ago and am proud of its accomplishments and grateful for the devotion of the

LRI’s backers to providing research support for talented scientists.

THE OFFICE OF AIDS RESEARCH

Acquired immunodeficiency syndrome (AIDS) appeared literally as a modern scourge. First rec-

ognized in 1981, it spread like wildfire in several vulnerable communities in the United States and

elsewhere. The demonstration that the cause is a virus led to an avalanche of research on the biol-ogy of the agent and to hopes for the quick development of a vaccine. However, by 1992, although

progress had been made that would later lead to important therapies, the advocacy community

was deeply depressed and had concluded that little had been accomplished despite considerableresearch investment, particularly in the United States. They attributed the apparent poor progressto a lack of central planning for the use of HIV/AIDS research resources and to the scattershot

use of the available funds. Based on this, AIDS advocates vigorously lobbied the US Congress tocreate a mechanism to correct both of these apparent deficiencies.

In 1993, Congress strengthened the existing NIH Office of AIDS Research (OAR) and chargedit with creating a unified plan for all NIH-sponsored AIDS research. They further directed the


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OAR to determine how all appropriated resources for AIDS research would be utilized, in accor-

dance with the plan it was to develop.In 1994, Bernard Fields, chair of the Department of Microbiology and Molecular Biology at

Harvard Medical School and a leader in the field of viral pathogenesis, published an influential op-edinthe New York Times where he called for a back-to-basics approach for the study of HIV/AIDS

This piece galvanized the research and advocacy communities.Harold Varmus had been appointed NIH director in 1993 and had to confront the particularly

vexing issues of designating an OAR director and seeing that the OAR met its congressionamandate. Furthermore, the NIH was not happy with the OAR having leadership responsibilities

for determining how HIV resources would be utilized. Such issues were traditionally determinedby the individual NIH institutes, a mechanism that had functioned well in the past.

Harold created a search committee for the OAR director, and I was asked to serve on it.

Although we received many nominations, most were not suitable for one reason or anotherHowever, among the nominees was Bernard Fields. He was clearly an outstanding candidate for

this position. The search committee was unanimous in their enthusiasm for him as OAR director. There was one “hitch.” Bernie had had pancreatic cancer that was now in remission. He explained

to the search committee that he would enthusiastically accept the position if it was offered butthat he had a CAT scan scheduled the next day, which he hoped would show him to be cancer-

free. Unfortunately, that exam showed a recurrence. Bernie carried on bravely andmade importantcontributions to the progress of AIDS research, but he clearly could not take up the responsibilities

of the OAR directorship. He died in January 1995. This left Harold Varmus in a difficult position, and he evidently cast around for a suitable

solution. He asked me to resign from the search committee and to submit my name as a candidate

After considerable soul-searching, I agreed to do so, recognizing the obligation each of us hadto do his utmost to control this disease. In the end, I was offered the position and accepted it

beginning my four-year tenure at OAR in February 1994. We needed to hit the ground running. Within the first two weeks of my appointment, we

convened a meeting, at the NIH Stone House, of leading figures in virology, immunology, andrelated disciplines, including Harold Varmus, David Baltimore, and Phil Sharp. Although much of

importance was discussed at this meeting, the central message was that we needed to get a handleon all of AIDS research as quickly as possible.To do this, a comprehensive review of the entire field

was essential. This proved to be a massive undertaking, but we set upon it immediately and had thegood fortune to recruit Arnold Levine, then chairman of the Department of Molecular Biology

at Princeton and the discoverer of p53, to chair what would come to be known as the Levine

Committee. Indeed, the “Levine Report,” when issued, set the ground rules for HIV researchthen, and its impact continues to be felt.

Nonetheless, we couldn’t wait for the results of the evaluation of all AIDS research and forthe recommendations of the Levine Committee. We set to work on a plan that would not be

proscriptive but would guide the field in what we (and, of course, a host of advisers) believed tobe promising directions. We also prioritized an increase in the proportion of the budget that was

targeted at investigator-initiated research grants.

Just as I came into the OAR, the first great success in combatting AIDS was achieved. It wasshown that treatment of infected women during pregnancy and of their babies in the neonatalperiod could almost eliminate mother-to-child transmission of the virus (53). This was a great

accomplishment that solidified in the minds of the advocacy community the value of scientifi-cally based study of HIV. They became even more supportive of the OAR. Their contributions

to advancing the research agenda were significant. Somewhat later, the HIV protease inhibitors

appeared, and they, together with the earlier developed reverse transcriptase inhibitors, allowed

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the introduction of what was called highly active antiretroviral therapy (HAART), which revolu-

tionized the management of infected individuals in the developed world and held out the prospect that the disease could be controlled, at least in part, by drugs that had been developed based on

fundamental research on the biology of the virus and the pathogenesis of the disease. These werestunning accomplishments for which the AIDS research community, NIH research support, and

the pharmaceutical industry deserve enormous credit! These achievements also gave the OAR the credibility to continue its efforts to guide the AIDS

research enterprise. Despite my satisfaction with this progress and with the contributions of theOAR, I was increasingly anxious to get back to being a full-time LI scientist. I had kept my lab

going during my tenure at the OAR, although it was getting progressively smaller. Nonetheless,some very good work was done in that period, including Tomo Yoshimoto’s discovery that NKT

cells rapidly produced cytokines, particularly IL-4, in response to in vivo stimulation (54) and the

work by Achsah Keegan, Keats Nelms, and John Ryan to dissect the signaling motifs within theIL-4 receptor cytosolic domain (55, 56). I had also kept my position as LI laboratory chief, but

this was only possible because of the generosity of Ron Germain who, as deputy LI lab chief, hadtaken on many of the responsibilities that I normally discharged.

Thus, after three years, I considered whether it was the right time to step down as OAR director,but I was deeply troubled by the poor progress being made in HIV vaccine development. I resolved

to spend at least another year in the effort to turn this around. During the OAR planning process,I strongly advocated and obtained a striking increase in the resources devoted to HIV vaccine

research. Also, in 1996, on World AIDS Day—December 1—a rare opportunity presented itself.President Clinton called into the White House several government leaders from the HIV research

effort to bring him up to date and to make necessary recommendations. Although I had had an

opportunity to speak to the president before about the need for an HIV vaccine (Figure 4), thechancetodosointheWhiteHousewasanexceptionalone.AttheWhiteHousemeetingonWorld

AIDS Day were Helene Gayle—then at the Centers for Disease Control and Prevention—Harold Varmus, Anthony Fauci, and me. Each of us was to have a short period to brief the president. I was

to be last, and because the meeting had started late, I was warned that I might not have a chanceto speak. Nonetheless, fate intervened and I did get my few minutes of face time during which I

made the case for doing our utmost to develop an HIV vaccine. This struck a responsive chord,and Mr. Clinton became a supporter of the vaccine effort.

A key element of the vaccine research strategy, in addition to substantial increases in the numberof research grants and the amount of money devoted to the study of potential vaccine approaches,

was the creation of the NIH Vaccine Research Center (VRC). I proposed this in early 1997, after

much discussion with Ron Germain, and the NIH leadership, particularly Harold Varmus and Tony Fauci, got solidly behind it. Harold brought the ideas to the House and Senate Appropri-

ations Subcommittee chairs John Porter and Arlen Specter, and we received an appropriation tobuild the building, which is now the Dale and Betty Bumpers Vaccine Research Center (Building

40) on the NIH campus. Although Congress had acted in record time, the appropriated funds were not sufficient to build what we believed was the optimal laboratory building for the purpose.

Fortunately, resources available to the OAR could be used to supplement the appropriation, and

the hoped-for building was indeed built. The OAR provided the resources for the operation of the VRC through its control of the NIH plan for AIDS research. And so the VRC was launchedand has been a major player in the vaccine development effort ever since.

By late 1997, I had been OAR director for almost four years, which had been filled with effort,satisfactions, and inevitable disappointments. Overall, I was enormously pleased I had taken on

the responsibility, but I was convinced that if I did not return full time to the LI in the near future,

I would have great difficulty continuing to be a productive laboratory scientist. So, in November


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Figure 4

Stressing the importance of developing an HIV vaccine while meeting President Clinton at NIH.

1997, I resigned the directorship and returned to my comfortable office and lab on the eleventhfloor of Building 10.

BACK TO THE LAB

I will not describe the period between 1998 and 2013 in the same detail I have given to former years, except to note that I continued to be very fortunate in terms of research colleagues. Two of

my postdocs from this era, Joshua Milner and Jinfang Zhu, have been appointed to PI positions

in NIAID, joining Bob Seder, who had been appointed earlier and is now a major figure in the VRC. They and many others did important work during their postdoctoral period.

I have continued to be interested in the process of Th differentiation and with my colleagues

have made many contributions to understanding this key step in lymphocyte biology. Among themare the analysis, with Hidehiro Yamane, of the positive feedback regulation of Th differentiation(57); with Jeff Zhu and Ryoji Yagi, of the transcriptional regulation of Th differentiation (58

59); with Lilly Guo, of the probabilistic control of IL-4 expression (60); with Booki Min and Josh Milner, of the role of repertoire complexity in controlling homeostasis, autoimmunity, and

autoinflammation (61, 62); with Zami Ben-Sasson, of the central role of IL-1 in determiningexpansion of responding CD4 and CD8 T cells (63); and with Lilly Guo, of the innate activation

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of cells of the adaptive immune system (64). The impact of these studies in the long run is still to

be determined.

Working with Postdocs

Earlier I referred to the experience of working with talented postdocs and the pleasure of watchingan idea come to fruition as a realized accomplishment. The reader will recognize that I have mainly

worked with postdocs, having had only one PhD student, Evelyn Rabin. Scientists have their ownstyles of working with postdocs. Mine has very much been interacting with talented and strong-

minded people who are not afraid to make their points and to challenge me. I have always foundthe interaction enormously stimulating and one that leads to a far better research plan than I would

have come up with on my own or, I believe, that the postdoc in question would have developed.

Also, this interaction is valuable for the postdoc, who must develop the independence necessary for his or her future career as a PI.

I must confess to have been less successful in situations in which a great deal of hand-holding was needed, and I have discouraged individuals who needed this type of support from joining

my group. But for those with the right turn of mind, quite independently of their degree of preparation and their technical skills, I believe that the mentor-trainee interaction I favor can be

an extremely effective way to nurture talented individuals. Indeed, my emphasis in this article onpostdoc accomplishments at the LI indicates how central they have been to the success of the

laboratory and how proud my colleagues and I are of their accomplishments in their post-LI days.

Long-Term Colleagues

I have been fortunate to have had a stable set of close colleagues over my long tenure at NIH. I have

already mentioned Ira Green, Ethan Shevach, Ron Schwartz, Ron Germain, David Margulies,and Rose Mage, who have been enormously important to me as colleagues and as individuals with

whom to exchange ideas and challenge assumptions. Two other LI colleagues must be mentioned: Mike Lenardo, whom we recruited from David Baltimore’s group at MIT, has been an enormous

strengthasaPIattheLI;andMishaSitkovsky,whocametousfromHermanEisen’sgroupatMIT,enjoyed great success at the LI and subsequently returned to Boston to pursue the development

of therapies that he deemed difficult to do at NIH. Two more long-standing colleagues with whom I have worked closely are Zami Ben-Sasson and

Zvi Grossman. Zami first joined my group as a postdoc in the 1970s and has worked on an adjunct basis with me in the time he could spare from his position as a senior professor at the Hebrew

University/Hadassah Medical Center. Zami is a remarkable scientist and has been responsible formany advances, including his role with Graham LeGros in determining the feedback regulation of

Th2 differentiation and his initiation of our program on the function of IL-1β as a direct activator

of the expansion of antigen-stimulated CD4 and CD8 T cells.Zvi and I have worked together since the early 1990s when we first proposed responsiveness

tuning as a key regulator of T cell homeostasis and activation (65). Zvi was trained as a physicist

and has a deep understanding of the dynamic function of the immune system. He too has been anadjunct at the LI, working here in the time he could make available from his responsibilities as aprofessor in the Sackler School of Medicine of Tel Aviv University.

I have had the good fortune to work with remarkable laboratory associates and office staff, who have had long tenures. Jane Hu-Li and Cyndy Watson joined my group in 1984. Cyndy

managed my lab with grace and excellent judgment and was a terrific technologist. Jane is one of the very best scientists with whom I have worked. She still sets the pace for the lab after 30 years.


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Cyndy retired in 2007; Xi Chen has filled her slot admirably. Kay McMahon and Effie Reyes have

provided me with unparalleled leadership at the LI office. Kay served as my secretary (althougheveryone knew she was the true lab chief) from 1981 until her retirement. Effie joined the LI in

1987, right out of high school. She took over as lab chief’s secretary on Kay’s retirement in 1997and still holds forth. Our editorial assistant, Shirley Starnes, came to the LI in 1979 and only now

plans to retire. Even more remarkably, Clarence Jackson, who prepared our sterile glassware andcarried out a series of other functions, was the longest-serving employee in the entire Department

of Health and Human Services on his retirement and continues to work at the LI as a contractoron a part-time basis.

A Word About Institutions

Great advances in science are the work of individuals and the research groups they assemblearound themselves. Notwithstanding this, the importance of institutions cannot be overlooked. I

have been nurtured by the intramural research program of the NIH for my entire independent

scientific career. The leadership of the NIH intramural research program has had a critical role infostering the achievements of the scientists who work within it. We sometimes forget how critical

distinguished leadership can be in enabling talented scientists to achieve remarkable advances.

On this subject, I’d like to comment on the NIH immunology community. When I arrived inBethesda as a clinical associate in 1962, there were few immunologists at NIH; the situation hadnot changed greatly on my return in 1968, although by then several younger scientists, including

Michael Potter, Tom Waldmann, and Henry Metzger, all later elected to the National Academyof Sciences, had begun what would prove to be remarkably important work.

To have watched and contributed to the expansion and flowering of the NIH immunologyresearch community over the decades has been truly gratifying. Immunology is now one of the

largest and possibly the most recognizeddiscipline on the NIH campus. The Immunology Interest

Group is the largest and probably the most active. It contributes to the training experience, it helpsfoster the work of individual scientists, and it is a mechanism to develop a consensus as to what

needs to be done to promote the continued health of the field. The growth and success of the

community has been the effort of many scientists; I won’t mention them by name partly becausethere are so many and partly for fear of leaving out a key figure. That has given NIH a mostremarkable spirit of joint action and collaboration. It has been a privilege to be a member of this

research community.

LAST WORDS

I began this article with the analogy of “catching the wave” and end it with a reference to the title,

“Endless Fascination.” I have been remarkably fortunate to have found a subject relatively early inlife that would keep on growing and changing and that would display new facets, new challenges,

and new opportunities. Those among you who have had a similar “romance” with a subject will

appreciate this.I close by addressing a final issue. Immunology is a fascinating subject, and one might justify

a lifetime’s devotion to it based simply on the continued intellectual challenges it provides. But

I have always found unconvincing the claim that scientists should be supported simply so thatthey can satisfy their curiosity. A worthy subject must offer more at the end of the day than

the satisfaction of curiosity. In that, we immunologists are fortunate because advances in ourfield have already contributed remarkably to human health, and a deeper understanding of the

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immune system’s mechanistic basis has the potential to contribute even more to the well-being of

humankind. Although this risks being a clich ´ e, I believe it nonetheless to be true. There is in Judaism the concept of “tikun olam” [ ], usually translated as “healing the

world” but which I prefer to think of as “perfecting the world.” Each of us has the responsibility to contribute to such “perfecting.” A career in immunology certainly qualifies!

DISCLOSURE STATEMENT

The author is not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

I thank all those who have contributed to the work I described here, and I ask the forbearance of

my colleagues whom I was unable to mention because of space limitations. I particularly thank Erin Wait, both for her help in editing this article and for her wonderful service as the production

editor for ARI. The research described here was supported by the Division of Intramural Researchof the National Institute of Allergy and Infectious Diseases through projects Z01-AI000493-27,

Z01-AI000926-11, Z01-AI000968-08, and Z01-AI000969-08. I particularly thank my wife Mar-ilyn for her unfailing support and encouragement and most of all for her excellent advice and

judgment, often getting me on the right track when my own approach would probably have lednowhere.

LITERATURE CITED

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Nature 197:193–94

2. Paul WE, Cohen AS. 1963. Electron microscopic studies of amyloid fibrils with ferritin-conjugated an-

tibody. Am. J. Pathol. 43:721–30

3. Li MC, Hertz R, Bergenstal DM. 1958. Therapy of choriocarcinoma and related trophoblastic tumors

with folic acid and purine antagonists. N. Engl. J. Med. 259:66–67

4. Odell WD, Wilber JF, Paul WE. 1965. Radioimmunoassay of thyrotropin in human serum. J. Clin.

Endocrinol. Metab. 25:1179–88

5. Paul WE,OdellWD. 1964. Radiationinactivation of theimmunological andbiological activities of human

chorionic gonadotropin. Nature 203:979–80

6. Paul WE, Ross GT. 1964. Immunologic cross-reaction between human chorionic gonadotropin and

human pituitary gonadotropin. Endocrinology 75:352–58

7. Paul WE, Kastin AJ, Odell WD. 1965. The effect of ionizing radiation on melanocyte-stimulating and

steroidogenic activities of corticotropin. Biochim. Biophys. Acta 100:263–69

8. Goldstein JL, Brown MS. 2012. History of science. A golden era of Nobel laureates. Science 338:1033–34

9. Germain RN, Paul WE. 2011. Baruj Benacerraf (1920–2011). Nature 477:34

10. Dutton RW, Eady JD. 1964. An in vitro system for the study of the mechanism of antigenic stimulationin the secondary response. Immunology 7:40–53

11. Paul WE, Siskind GW, Benacerraf B. 1966. Studies on the effect of the carrier molecule on anti-hapten

antibody synthesis. II. Carrier specificity of anti-2,4-dinitrophenyl-poly-L-lysine antibodies. J. Exp. Med.

123:689–705

12. Paul WE, Siskind GW, Benacerraf B. 1968. Specificity of cellular immune responses. Antigen concentra-

tion dependence of stimulation of DNA synthesis in vitro by specifically sensitized cells, as an expression

of the binding characteristics of cellular antibody. J. Exp. Med. 127:25–42


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13. Mitchison NA. 1971. The carrier effect in the secondary response to hapten-protein conjugates. I.

Measurement of the effect with transferred cells and objections to the local environment hypothesis

Eur. J. Immunol. 1:10–17

14. Katz DH, Paul WE, Goidl EA, Benacerraf B. 1970. Carrier function in anti-hapten antibody responses

I. Enhancement of primary and secondary anti-hapten antibody responses by carrier preimmunization

J. Exp. Med. 132:261–82

15. Paul WE, Katz DH, Goidl EA, Benacerraf B. 1970. Carrier function in anti-hapten immune responses

II. Specific properties of carrier cells capable of enhancing anti-hapten antibody responses. J. Exp. Med

132:283–9916. Davie JM, Paul WE. 1971. Receptors on immunocompetent cells. II. Specificity and nature of receptors

on 2,4-dinitrophenyl guinea pig albumin-125I binding lymphocytes of normal guinea pigs. J. Exp. Med

134:495–516

17. Shevach EM, Paul WE, Green I. 1972. Histocompatibility-linked immune response gene function in

guinea pigs: specific inhibition of antigen-induced lymphocyte proliferation by alloantisera. J. Exp. Med

136:1207–21

18. Rosenthal AS, Shevach EM. 1973. Function of macrophages in antigen recognition by guinea pig

T lymphocytes. I. Requirement for histocompatible macrophages and lymphocytes. J. Exp. Med

138:1194–1212

19. Shevach EM, Rosenthal AS. 1973. Function of macrophages in antigen recognition by guinea pig

T lymphocytes. II. Role of the macrophage in regulation of genetic control of the immune response

J. Exp. Med. 138:1213–29

20. Schwartz RH, PaulWE. 1976. T lymphocyte-enriched murine peritoneal exudate cells. II. Genetic contro

of antigen-induced T lymphocyte proliferation. J. Exp. Med. 143:529–40

21. Glimcher LH, Sharrow SO, Paul WE. 1983. Serologic and functional characterization of a panel of

antigen-presenting cell lines expressing mutant I-A class II molecules. J. Exp. Med. 158:1573–88

22. van Boxel JA, Paul WE, Terry WD, Green I. 1972. IgD-bearing human lymphocytes. J. Immunol

109:648–51

23. Sieckmann DG, Asofsky R, Mosier DE, Zitron I, Paul WE. 1978. Activation of mouse lymphocytes by

anti-immunoglobulin. I. Parameters of the proliferative response. J. Exp. Med. 147:814–29

24. Sieckmann DG, Scher I, Asofsky R, Mosier DE, Paul WE. 1978. Activation of mouse lymphocytes by

anti-immunoglobulin. II. Requirement for a mature subset of B lymphocytes. J. Exp. Med. 148:1628–4325. Sharon R, McMaster PRB, Kask AM, Owens JD, Paul WE. 1975. DNP-Lys-Ficoll: a T-independen

antigen which elicits both IgM and IgG anti-DNP antibody secreting cells. J. Immunol. 114:1585–89

26. DeFranco AL, Raveche ES, Asofsky R, Paul WE. 1982. Frequency of B lymphocytes responsive to anti-immunoglobulin. J. Exp. Med. 155:1523–36

27. Howard M, Farrar J, Hilfiker M, Johnson B, Takatsu K, et al. 1982. Identification of a T-cell derived

B-cell growth factor distinct from interleukin 2. J. Exp. Med. 155:914–23

28. Ohara J, Coligan J, Zoon K, Maloy WL, Paul WE. 1987. High efficiency purification and chemical

characterization of B cell stimulatory factor-1/interleukin-4. J. Immunol. 139:1127–34

29. Isakson PC, Pur ´ e E, Vitetta ES, Krammer PH. 1982. T cell-derived B cell differentiation factor(s). Effec

on the isotype switch of murine B cells. J. Exp. Med. 155:734–48

30. Vitetta ES, Ohara J, Myers C, Layton J, Krammer PH, Paul WE. 1985. Serologic, biochemical and

functional identity of B cell stimulatory factor-1 and B cell differentiation factor for IgG1. J. Exp. Med

162:1726–31

31. Coffman RL,Ohara J, Bond MW, Carty J, Zlotnik A, Paul WE. 1986. B cell stimulatory factor-1 enhances

the IgE response of lipopolysaccharide-activated B cells. J. Immunol. 136:4538–4132. Davis MM, Cohen DI, Nielsen EA, DeFranco AL, Paul WE. 1982. The isolation of B and T cell–specific

genes. In B and T Cell Tumors: Biological and Clinical Aspects. UCLA Symposia on Molecular and Cellular

Biology, Vol. XXIV, ed. E Vitetta, CF Fox, pp. 215–20. New York: Academic

33. Hedrick SM, Cohen DI, Nielsen EA, Davis MM. 1984. Isolationof cDNA clones encoding T cell-specific

membrane-associated proteins. Nature 308:149–53

34. Hedrick SM,Nielsen EA,Kavaler J, Cohen DI,DavisMM. 1984. Sequence relationships between putative

T-cell receptor polypeptides and immunoglobulins. Nature 308:153–58

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35. Snapper CM, Paul WE. 1987. Interferon gamma and B cell stimulatory factor-1 reciprocally regulate Ig

isotype production. Science 236:944–47

36. Finkelman FD, Kotana I, Urban J, Snapper C, Ohara J, Paul WE. 1986. Suppression of in vivo polyclonal

IgE responses by monoclonal antibody to the lymphokine BSF-1. Proc. Natl. Acad. Sci. USA 83:9675–78

37. Brown MA, Pierce JH, Watson CJ, Falco J, Ihle JN, Paul WE. 1987. B cell stimulatory factor-

1/interleukin-4 mRNA is expressed by normal and transformed mast cells. Cell 50:809–18

38. Plaut M, Pierce JH, Watson CJ, Hanley-Hyde J, Nordan RP, Paul WE. 1989. Mast cell lines produce

lymphokines in response to cross linkage of FcεRI or to calcium ionophores. Nature 339:64–67

39. Seder RA, Paul WE, Dvorak AM, Sharkis SJ, Kagey-Sobotka A, et al. 1991. Mouse splenic and bonemarrow cell populations that express high affinity Fcε receptors and produce IL-4 are highly enriched in

basophils. Proc. Natl. Acad. Sci. USA 88:2835–39

40. LeGros G, Ben-Sasson SZ, Seder R, Finkelman FD, Paul WE. 1990. Generation of IL-4-producing cells

in vivo and vitro. IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J. Exp. Med.

172:921–29

41. Swain SL, Weinberg AD, English M, Huston G. 1990. IL-4 directs the development of Th2-like helper

effectors. J. Immunol. 145:3796–806

42. Seder RA, Paul WE, Davis MM, Fazekas de St. Groth B. 1992. The presence of interleukin 4 during

in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor

transgenic mice. J. Exp. Med. 176:1091–98

43. Hsieh CS, Heimberger AB, Gold JS, O’Garra A, Murphy KM. 1992. Differential regulation of T helper

phenotype development by interleukins 4 and 10 in an αβ T-cell-receptor transgenic system. Proc. Natl. Acad. Sci. USA 89:6065–69

44. Seder RA, Gazzinelli R, Sher A, Paul WE. 1993. Interleukin 12 acts directly on CD4+ T cells to enhance

priming for interferon γ production and diminishes interleukin 4 inhibition of such priming. Proc. Natl.

Acad. Sci. USA 90:10188–92

45. Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O’Garra A, Murphy KM. 1993. Development of TH1

CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260:547–49

46. Yamane H, Paul WE. 2013. Early signaling events that underlie fate decisions of naive CD4+ T cells

toward distinct T-helper cell subsets. Immunol. Rev. 252:12–23

47. Paul WE, Seder RA. 1994. Lymphocyte responses and cytokines. Cell 76:241–51

48. Dustin ML. 2009. Modular design of immunological synapses and kinapses. Cold Spring Harb. Perspect.

Biol.1:a002873

49. Paul WE. 1981. Clinical investigation—On the threshold of a golden era? J. Clin. Investig. 68:823–2650. Paul WE, ed. 1984. Fundamental Immunology. New York: Raven Press. 809 pp.

51. Paul WE, ed. 2012. Fundamental Immunology. Philadelphia: Lippincott, Williams & Wilkins. 7th ed.

1283 pp.

52. Paul WE, Fathman CG, Metzger H, eds. 1983. Annual Review of Immunology, Vol. 1. Palo Alto, CA:

Annual Reviews. 666 pp.

53. Mofenson L, Balsley J, Simonds RJ, Rogers MF, Moseley RR. 1994. Recommendations of the U.S.

Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human

immunodeficiency virus. Morb. Mortal. Wkly. Rep. 43:1–15

54. Yoshimoto T, Paul WE. 1994. CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response

to in vivo challenge with anti-CD3. J. Exp. Med. 179:1285–95

55. Keegan AD, Nelms K, White M, Wang L-M, Pierce JH, Paul WE. 1994. An IL-4 receptor region

containing an insulin receptor motif is important for IL-4-mediated IRS-1 phosphorylation and cellgrowth. Cell 76:811–20

56. Ryan JJ, McReynolds LJ, Keegan A, Wang L-H, Garfein E, et al. 1996. Growth and gene expression are

predominantly controlled by distinct regions of the human IL-4 receptor. Immunity 4:123–32

57. Yamane H, Paul WE. 2005. Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells

to generate a Th2-inducing cytokine environment. J. Exp. Med. 202:793–804

58. Zhu J, Yamane H, Paul WE. 2010. Differentiation of effector CD4 populations. Annu. Rev. Immunol.

28:445–89


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59. Yagi R, Zhu J, Paul WE. 2011. An updated view on transcription factor GATA3-mediated regulation of

Th1 and Th2 cell differentiation. Int. Immunol . 23:415–20

60. Guo L, Hu-Li J, Paul WE. 2004. Probabilistic regulation of IL-4 production in Th2 cells: accessibility at

the Il4 locus. Immunity 20:193–203

61. Min B, McHugh R, Sempowski GD, Mackall C, Foucras G, Paul WE. 2003. Neonates support

lymphopenia-induced proliferation. Immunity 18:131–40

62. Milner JD, Ward J, Keane-Myers A, Paul WE. 2007. Specificity-based lymphocyte competition in

“homeostatic” and antigen-driven proliferation. Proc. Natl. Acad. Sci. USA 104:576–81

63. Ben-Sasson SZ, Hu-Li J, Quiel J, Cauchetaux S, Ratner M, et al. 2009. IL-1 acts directly on CD4 T cellsto enhance their antigen-driven expansion and differentiation. Proc. Natl. Acad. Sci. USA 106:7119–24

64. Guo L, Wei G, Zhu J, Liao W, Leonard W, et al. 2009.IL-1 family members and STAT activators induce

cytokine production by Th2, Th17 and Th1 cells. Proc. Natl. Acad. Sci. USA 106:13463–68

65. Grossman Z, Paul WE. 1992. Adaptive cellular interactions in the immune system: the tunable activation

threshold and the significance of subthreshold responses. Proc. Natl. Acad. Sci. USA 89:10365–69

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Annual Review o

Immunology

Volume 32, 2014Contents

Endless Fascination

William E. Paul 1

The Interaction Between Signal Regulatory Protein Alpha (SIRPα ) and

CD47: Structure, Function, and Therapeutic Target

A. Neil Barclay and Timo K. van den Berg 25

TGF-β Activation and Function in Immunity

Mark A. Travis and Dean Sheppard 51

Tyrosine Phosphatase PTPN22: Multifunctional Regulator of Immune

Signaling, Development, and Disease Nunzio Bottini and Erik J. Peterson 83

γδ T Cells: First Line of Defense and Beyond

Yueh-hsiu Chien, Christina Meyer, and Marc Bonneville 121

Malaria Immunity in Man and Mosquito: Insights into Unsolved Mysteries

of a Deadly Infectious Disease

Peter D. Crompton, Jacqueline Moebius, Silvia Portugal, Michael Waisberg,

Geoffrey Hart, Lindsey S. Garver, Louis H. Miller,

Carolina Barillas, and Susan K. Pierce 157

Adoptive Immunotherapy for Cancer or Viruses Marcela V. Maus, Joseph A. Fraietta, Bruce L. Levine, Michael Kalos,

Yangbing Zhao, and Carl H. June 189

Immunology of Psoriasis

Michelle A. Lowes, Mayte Su ´ arez-Fari˜ nas, and James G. Krueger 227

Immunology of Relapse and Remission in Multiple Sclerosis

Lawrence Steinman 257

Transcriptional Control of Early T and B Cell Developmental Choices

Ellen V. Rothenberg 283

Biology of CD1- and MR1-Restricted T Cells

Mariolina Salio, Jonathan D. Silk, E. Yvonne Jones, and Vincenzo Cerundolo 323

Microglia Development and Function

Debasis Nayak, Theodore L. Roth, and Dorian B. McGavern 367

v

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The Aryl Hydrocarbon Receptor: Multitasking in the Immune System

Brigitta Stockinger, Paola Di Meglio, Manolis Gialitakis, and Jo˜ ao H. Duarte 403

Complement and Its Receptors: New Insights into Human Disease

V. Michael Holers 433

Innate Immune Sensing and Signaling of Cytosolic Nucleic Acids

Jiaxi Wu and Zhijian J. Chen 461

Chromatin Contributions to the Regulation of Innate Immunity

Stephen T. Smale, Alexander Tarakhovsky, and Gioacchino Natoli 489

Interferon-Stimulated Genes: A Complex Web of Host Defenses

William M. Schneider, Meike Dittmann Chevillotte, and Charles M. Rice 513

Systems-Level Analysis of Innate Immunity

Daniel E. Zak, Vincent C. Tam, and Alan Aderem 547

Antigen Presentation in the Autoimmune Diabetes of the NOD Mouse

Emil R. Unanue 579

Metabolic Regulation of Immune Responses Kirthana Ganeshan and Ajay Chawla 609

Anticytokine Autoantibody–Associated Immunodeficiency

Sarah K. Browne 635

Chemokines and Chemokine Receptors: Positioning Cells for Host Defense

and Immunity

Jason W. Griffith, Caroline L. Sokol, and Andrew D. Luster 659

Indexes

Cumulative Index of Contributing Authors, Volumes 22–32 703

Cumulative Index of Article Titles, Volumes 22–32 709

Errata

An online log of corrections to Annual Review of Immunology articles may be found at

http://www.annualreviews.org/errata/immunol

vi C on te nt s

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ANNUAL REVIEWSIt’s about time. Your time. It’s time well spent.

New From Annual Reviews:

Annual Review of Statistics and Its Application Volume 1 • Online January 2014 • http://statistics.annualreviews.org

Editor: Stephen E. Fienberg, Carnegie Mellon University

Associate Editors: Nancy Reid, University of Toronto

Stephen M. Stigler, University of Chicago

The Annual Review of Statistics and Its Application aims to inform statisticians and quantitative methodologists

well as all scientists and users of statistics about major methodological advances and the computational tools t

allow for their implementation. It will include developments in the eld of statistics, including theoretical statistic

underpinnings of new methodology, as well as developments in specic application domains such as biostatist

and bioinformatics, economics, machine learning, psychology, sociology, and aspects of the physical sciences

Complimentary online access to the frst volume will be available until January 2015.

TABLE OF CONTENTS:

• What Is Statistics? Stephen E. Fienberg

• A Systematic Statistical Approach to Evaluating Evidence

from Observational Studies, David Madigan, Paul E. Stang,

Jesse A. Berlin, Martijn Schuemie, J. Marc Overhage,

Marc A. Suchard, Bill Dumouchel, Abraham G. Hartzema,

Patrick B. Ryan

• The Role of Statistics in the Discovery of a Higgs Boson,

David A. van Dyk

• Brain Imaging Analysis, F. DuBois Bowman

• Statistics and Climate, Peter Guttorp

• Climate Simulators and Climate Projections,

Jonathan Rougier, Michael Goldstein

• Probabilistic Forecasting, Tilmann Gneiting,

Matthias Katzfuss

• Bayesian Computational Tools, Christian P. Robert

• Bayesian Computation Via Markov Chain Monte Carlo,

Radu V. Craiu, Jerey S. Rosenthal

• Build, Compute, Critique, Repeat: Data Analysis with Latent

Variable Models, David M. Blei

• Structured Regularizers for High-Dimensional Problems:Statistical and Computational Issues, Martin J. Wainwright

• High-Dimensional Statistics with a View Toward Applicat

in Biology, Peter Bühlmann, Markus Kalisch, Lukas Meie

• Next-Generation Statistical Genetics: Modeling, Penaliza

and Optimization in High-Dimensional Data, Kenneth Lan

Jeanette C. Papp, Janet S. Sinsheimer, Eric M. Sobel

• Breaking Bad: Two Decades of Life-Course Data Analysi

in Criminology, Developmental Psychology, and Beyond,

Elena A. Erosheva, Ross L. Matsueda, Donatello Telesca

• Event History Analysis, Niels Keiding

• Statistical Evaluation of Forensic DNA Prole Evidence,

Christopher D. Steele, David J. Balding

• Using League Table Rankings in Public Policy Formation

Statistical Issues, Harvey Goldstein

• Statistical Ecology, Ruth King

• Estimating the Number of Species in Microbial Diversity

Studies, John Bunge, Amy Willis, Fiona Walsh

• Dynamic Treatment Regimes, Bibhas Chakraborty,

Susan A. Murphy

• Statistics and Related Topics in Single-Molecule Biophys

Hong Qian, S.C. Kou• Statistics and Quantitative Risk Management for Banking

and Insurance, Paul Embrechts, Marius Hofert

Access this and all other Annual Reviews journals via your institution at www.annualreviews.or

annurev-immunol-032713-120247

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