1991 Ann Rev Immunol

8/3/2019 1991 Ann Rev Immunol

1/28

Annu. Rev. bnmunol.1991.9:271-96Copyright1991by AnnualReviews nc. All rights reserved

THE DENDRITIC CELLAND ITS ROLE INIMMUNOGENICITY

SYSTEM

Ralph M. SteinmanLaboratory of Cellular Physiology and ImmunologyandIrvington Institute, The Rockefeller University, NewYork,New York 10021KEYWORDS:primary immuneesponse, antigen presenting cells, Langerhanscells, homing, ntigen processing

AbstractDendritic cells are a system of antigen presenting cells that function toinitiate several immuneesponses such as the sensitization of MHC-restric-ted T cells, the rejection of organ transplants, and the formation of T-dependent antibodies. Dendritic cells are found in many nonlymphoidtissues but can migrate via the afferent lymphor the blood stream to theT-dependent areas of lymphoid organs. In skin, the immunostimulatoryfunction of dendritic cells is enhanced by cytokines, especially GM-CSF.After foreign proteins are administered in situ, dendritic cells are a prin-cipal reservoir of immunogen.n vitro studies indicate that dendritic cellsonly process proteins for a short period of time, when he rate of synthesisof MHCroducts and content of acidic endocytic vesicles are high. Antigenprocessing is selectively dampened fter a day in culture, but the capacityto stimulate responses to surface bound peptides and mitogens remainsstrong. Dendritic cells are motile, and efficiently cluster and activate Tcells that are specific for stimuli on the cell surface. High evels of MHCclass-I and -II products and several adhesins, such as ICAM-1 nd LFA-3, likely contribute to these functions. Therefore dendritic cells are spe-cialized to mediate several physiologic components of immunogenicity

~ Abbreviations: APC,antigen-presenting cell; LC, Langerhans cells; MLR,mixed leuko-cyte reaction; MHC,major histocompatibility complex.2710732-0582/91/0410-0271 $02.00

www.annualreviews.org/aronlineAnnual Reviews

Annu.R

ev.

Immunol.1991.9:271-296.D

ownloadedfroma

rjournals.annualreviews.org

byRockefellerUniversityon

08/15/07.

Forpersonaluseonly.
http://www.annualreviews.org/aronlinehttp://www.annualreviews.org/aronlinehttp://www.annualreviews.org/aronline


2/28

272 STEINMANsuch as the acquisition of antigens in tissues, the migration to lymphoidorgans, and the identification and activation of antigen-specific T cells.The function of these presenting cells in immunologicolerance is justbeginning o be studied.INTRODUCTIONManyissues contain a trace populationof cells with an unusualdendriticshape, high levels of MHClass-II products, and strong accessory unctionfor the stimulation of T lymphocytes.A clearer picture of the physiologyof these cells is emerging nd s reviewed ere. Dendritic cells comprisesystem that occupies discrete portions of nonlymphoid nd .lymphoidorgans and is interconnected by defined pathways f movementTable 1).In each site, dendritic cells share features of structure and function, themostnotable being the ability to capture antigens and initiate T celt-mediated mmunity.Themechanismsf dendritic cell action are importantfor understanding how T cells are primed and how one might beginto manipulate the immuneesponse at the early sensitization phase ofimmunity.Three areas of function are considered here, each exhibitingdifferences fromother antigen-presentingcells (APC): sentinel rolewhich ntigens are captured and presented, a migratoryfunction in whichdendritic cells move o the T-dependentareas of lymphoidorgans andbind antigen-specific T cells, and an adjuvant or activation role in whichT-cell growthand effector function are induced. Recent progress on den-dritic cells is reviewed ere. More etailed reports on manyopics are inResearch n Immunology olume 40, International Reviews n ImmunologyVolume , Advances n ImmunologyVolume 7, and EpidermalLangerhansCells, ed. G. Schuler.DENDRITIC CELLS: A WIDELY DISTRIBUTEDAND CONNECTED SYSTEM OF POTENT ANTIGEN-PRESENTING CELLSThecharacterizationof dendriticcells has required he isolation of enrichedpopulations f what s a trace cell type in all tissues. Mousepleen remains

Table 1 The dendritic cell system--distribution and nomenclatureNonlymphoid organs Langerhans ells, interstitial dendritic cellsCirculation Afferent lymphveiled cells, blood dendritic cellsLymphoid organs Lymphoidendritic cells, interdigitating cells


Annu.Re

v.

Immunol.1991.9:271-296.Downloadedfroma

rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


3/28

DENDRITIC CELLS 273the organ most readily analyzed, but manyother tissues have been utilizedsuccessfully. Typically, dendritic cells do not adhere to tissue culture sur-faces, especially after a day in culture, and they have low levels of Fcreceptors (FcR) but high levels of MHClass-II products. Macrophagesin contrast are adherent, with abundant FcR but variable levels of classII. We eview the isolation and function of dendritic cells in differentsites and include newevidence that these antigen-presenting cells captureantigens in situ and movefrom nonlymphoid to lymphoid organs.Nonlymphoid organsEPIDERMISpidermal Langerhans cells are the best characterized non-lymphoiddendritic cells. It is feasible to prepare partially enriched (30-60%)populations in mice, since keratinocytes can be depleted with ~-thy-1 and complement plus adherence (1, 2). Partially enriched Langerhansceils suffice in most studies of function and are a better starting materialfor purification by sorting and panning methods than are unfractionatedcells (2, 3). For human pidermis there is no mAbike c~-thy-1 which bindskeratinocytes, but anti-CD 1 mAb electively identify Langerhanscells (4).Mouse pidermal Langerhans cells, in spite of high levels of MHClass-II products and detectable FoR are not active antigen-presenting cellsfor the mixed lymphocyte reaction (MLR)or ~-CD3 esponse. Activitydevelops after a 1-3 day period of culture in which the cytokine GM-CSFplays a key role (2, 3, 5). GM-CSF oes not act simply to maintainLangerhans cell viability, since another cytokine, TNF-cachectin, main-tains viability without inducing accessory function (6). Structure andphenotype also change in culture. The Langerhans cells enlarge, expressmore MHClass-II and adhesion molecules (below), and lose Fc receptorsand Birbeck granules. Romani et al (7) and Teunissen et al (8) notedentirely analogous changes during the culture of humanLangerhans cells.As a result, cultured Langerhans cells fully resemble blood and lymphoiddendritic cells (1, 7, 9, 10).There is evidence that Langerhans cells can leave the skin and movevia the afferent lymph to draining lymphoid organs. Cells with Birbeckgranules have been noted in lymph (11, 12) and lymph node (13).contact allergens are applied, allergen is found 8-24 hr later on lymphoiddendritic cells (14). Larsen (15) directly monitored the movement fgerhans cells out of the epidermis. Grafting itself leads to movementneither syngeneic or allogeneic hosts. Within a day, the Langerhans cellsenlarge and express high levels of MHClass II. Epidermal Langerhanscells numbers fall to about one third steady state, and the antigen-pre-senting cells appear in the dermis in what appear to be lymphatics. Similarevents occur in organ cultures of skin fragments. Langerhans cells move


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


4/28

274 STE1NMANinto the dermis and then the culture medium 15). Kaplan et al suggestthat dermal Langerhans cells also arise from the blood in delayed typehypersensitivity reactions (16).HEARa" abre, Hart, and McKenzieshowed that the interstitium of mostorgans, except brain, contain irregularly shaped cells that stain stronglywith mAb o MHClass-II products and the CD45 eukocyte antigen (17-19). Twokinds of resident CD45leukocytes have been identified (20)with a new antimacrophage mAb: macrophages that react with the mAband are radioresistant, and dendritic cells that do not react with the mAbbut are strongly MHClass II-positive and are radiosensitive.Larsen et al, studying mousecardiac allografts, found that the numberof interstitial Ia dendritic cells fell during the first four days after grafting(21). Using mAb pecific to polymorphisms of the heart donor, they sawdonor-derived, MHClass II-rich dendritic cells in the spleen, indicatingmigration from the heart via the blood stream. These results were con-firmed in a rat limb transplant model(22).L~WrtExcept for an initial report (23), there has been little studyisolated dendritic cells. In situ these antigen-presenting cells are in theportal triads, in contrast to sinus-lining phagocytes Kupffer cells) (18, 20).LtrNG n rat (24, 25), mouse(26, 27), and human 28, 29), dendriticare selected on the basis of their low buoyant density, and lack of plasticadherence and FcR. The enriched ceils have abundant MHClass-II andinduce strong T cell-mediated immune esponses. The parenchyma s thesource of lung dendritic cells rather than the bronchoalveolar lavage fluid,a standard source of macrophages.Holt et al (30) localized dendriticcells to alveolar septae, as well as within and just beneath airwayepithelium. In tangential sections, the networkof epithelial dendritic cellsis reminiscent of epidermal Langerhans cells. Macrophages re juxtaposedto dendritic cells along the airway.After aerosolization of proteins, lung dendritic cells present antigen,since the isolated antigen-presenting cells directly stimulate antigen-specificT-cell lines (24). To detect antigen-presenting cells function, suppressivemacrophages must be removed.6tJa" Pavli et al succeeded in isolating dendritic cells from the laminapropria of mouse intestine (31). Again, depletion of suppressive macro-phages helped uncover the presence and function of dendritic cells.The CirculationAFF~R~NaLVraPr~ Afferent but not efferent lymph contains leukocytestermed "veiled" cells in rabbit (32), pig (33), rat (34, 35), mouse


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


5/28

DENDRITIC CELLS 275human 37), and sheep (38). Like dendritic cells, veiled cells have abuoyant density, low FcR and phagocytic activity, and high levels of MHCclass-II and antigen-presenting cell activity. The origin of veiled cells isunclear. They may come from the interstitium and epithelium of manyorgans, or from a pool of cells that leaves the blood, moves throughnonlymphoid issues, and enters the lymph.

If protein antigens are administered intradermally, afferent lymphden-dritic cells carry the antigen in a form that will trigger antigen-specific T-cell lines (38). Therefore, dendritic cells in lymphcan carry antigenslymphoid tissues, as has been proposed for epidermal Langerhans cells.BLOODn human blood, < 0.1% of the white cells are dendritic cells.Prior enrichment methods fell short of substantial purity, but >90%purity has nowbeen achieved (39). Enrichmententails successive depletionof T cells (sheep red cell rosetting), monocytesadherence o plastic orcoated plates), and B plus NKcells (pelleting in metrizamide). Together,and whenperformed in the above sequence, these steps yield an E rosettenegative, nonadherent, low-density fraction with 30--60%dendritic cells.Further purity is obtained by panning or sorting with mAb, especiallyto CD45RA,hat selectively react with the contaminants. Although thisisolation approach is labor-intensive, one simultaneously secures popu-lations of other cell types, each depleted of dendritic cells (39).

The purity of the populations can be assessed by three approaches withcomparable results. One approach uses mAband flow cytometry (39)phenotype the cell fractions. Markers hat dendritic cells lack are CD3 Tcells), CD14 monocytes), CD19/20 (B cells), and CD56/57 (NK cells).Abundantproteins are classoI and -II MHCroducts plus a distinct arrayof receptors and adhesion molecules (see below). The second approachto observe cell fractions live by video microscopy (39). Dendritic cellscontinually extend and retract large lamellipodia or "veils." Noother cellin blood shows his motility. The third approach is to test MLRtimulatoryfunction. The dendritic cells are potent, e.g. in cultures of 105 T cells,1-3 103 allogeneic dendritic cells induce an MLR omparable to thatinduced by the standard population of 105 bulk mononuclears. Monocytesand B cells have little or no stimulating activity (21).Dendritic cells in blood may be migrating from nonlymphoid issues tospleen. Evidence for the latter was recently obtained in a rodent hearttransplant model(39). Alternatively, dendritic cells maybe en route fromthe marrow o nonlymphoid tissues.Lymphoid OrgansTONSIL ubstantial purification of human onsil dendritic cells also hasbeen obtained (40). The cells are strong MLRtimulators, and their distinct


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


6/28

276 STEINMANsurface composition has been outlined with a panel of mAb nd immuno-peroxidase labeling. The results are included in the next section.T-DEPENDENT REGIONS OF PERIPHERAL LYMPHOID ORGANSIn sections ofthe T-dependent regions of lymphoid organs, there are "interdigitatingcells" (41) which resemble dendritic cells in cytology and phenotype (42,43). If dendritic cells from mousespleen (44) are administered intoblood or foot pads, Austyn et al noted homing to the T-dependent areas.Fossum njected radiolabeled afferent lymphdendritic cells into rats. Bylight and electron microscopy, the injected cells assumed he location ofinterdigitating cells (45). Little is known bout the efficiency of this homing.Possibly the only cells that are retained are those that find T cells specificto the presented antigens. The reason is that the flux of dendritic cells inlymphcan be 105/hr, yet these antigen-presenting cells do not accumulatein lymph node or efferent lymph. Given the substantial turnover of cellsin lymph and in spleen (35, 46), most dendritic cells may not live longupon reaching the lymphoid organ.

In spleen, dendritic cells are more numerous han the interdigitatingcells of the periarterial sheaths. When endritic cells are sorted from freshspleen suspensions (see below), only a subpopulation label clearly withNLDC14547), a mAbo interdigitating cells in the central periarterialsheaths (48). In section, nests of dendritic cells lie in the peripheryof theT area interrupting the marginal zone of macrophages (49, 50). Bothcells and antigens leave the arterial tree in the marginal zone, so in effect,dendritic cells are positioned like "doors" through whichT cells pass uponentry into the periarterial sheaths. Lymphoidorgans may contain twopopulations: peripheral [?migratory], short-lived dendritic cells, andcentral, long-lived interdigitating cells.DENDRITICCELLSFRESHLYSOLATED ROMMOUSE PLEENAS evidentabove, dendritic cell isolation requires many teps that can take a day ormore. Since viability and function can be influenced by cytokines like GM-CSF, IL-1, and TNF 2, 3, 6, 51, 52), it is important to characterize freshisolates. This recently was done in mouse spleen using a new mAb,N418to murine CD1 c (47, 49). Dendritic cells are the maincell expressing highlevels of CD1 c in the steady state in spleen. Fresh suspensions containabout 1.5% N418+ cells, while peritoneal washings and blood have few.Two-color immunolabelingshows that splenic N418+ cells have the pheno-type of dendritic cells (47). Sorted N418+ cells assume a typical veiledmorphology f cultured for a day.Fresh, sorted N418+ dendritic cells actively stimulate the MLR ndpresent protein antigens to sensitized T cells (47). If proteins are given i.v.


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


7/28

DENDRITIC CELLS 277or i.p., the N418+ fraction is the main source of immunogen hen spleenfractions are applied to antigen-specific T cells (53)."r~~ctJs Large, bone marrow-derived, class II-rich dendritic cells arefound in the medulla (54, 55). These ikely are the "interdigitating cells"noted by electron microscopy (56) or the "dendritic cells" in enzyme-digested thymus (57-59). Crowley et al succeeded in enriching mousethymic dendritic cells to a high degree of purity, using the same approachas was used in spleen (10). Adherent cells with a low buoyant density werecultured overnight so that most dendritic cells dislodged. The dendriticcells were about twice the size as in spleen but similar in phenotype andfunction. If mgdoses of proteins are given i.v., thymic dendritic cells pickup antigen in a form stimulatory for T cells (58).Summary." Dendritic Cell LineageNonlymphoidorgans, blood, afferent lymph, and lymphoid tissues (seeTable 1) contain dendritic cells with different namesbut similar properties.To enrich them, one selects for low buoyant density, nonadherence toplastic especially after a day in culture, and absence of certain markersfound on other cell types. These approaches simply deplete other cells butdo not positively select for cells that are distinct in shape and have abun-dant MHClass II plus strong antigen-presenting cell function. This indi-cates that the negatively selected dendritic cells are an independent celltype.Evidence s growing hat dendritic cells in different tissues, as definedmorphologically and by a distinct group of cell surface markers, are partof a system connected by movementand homing. Dendritic ceils in non-lymphoidorgans, such as epidermal Langerhanscells and heart interstitialcells, can give rise to "veiled cells" in the afferent lymphand blood whichmigrate to lymphoid tissues where they are isolated as "dendritic" or"interdigitating" cells. Coupled with these migratory abilities is thecapacity to capture antigens in an immunogenic orm in situ.It seemsappropriate to classify the cells in Table I as a separate lineagegiven their distinct features and tissue distribution. There is no evidencethat other white cells convert into dendritic cells or vice versa, even ifchallenged with a variety of cytokines. For example, macrophage andgranulocyte factors, M-CSF nd G-CSF, have no known effects on den-dritic cells, in contrast to their profound effects on typical phagocytes.Nonetheless, the progenitor for the putative dendritic cell lineage hasnot been isolated. Dendritic cells in spleen and lymph originate from aproliferating pool of precursors and undergo rapid turnover (35, 46, 60),but the site for proliferation (3H-thymidine uptake) is not known. A bone


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


8/28

278 STEINMANmarrow recursor exists (35, 46, 54, 61), but conditions have not beenidentified that direct its growthn culture.THE DENDRITIC CELL SURFACE:SPECIALIZATIONS FOR ANTIGEN PRESENTATIONIn mouse nd human, he fluorescence activated cell sorter (FACS) owhas provided etailed descriptionsof the dendritic cell surface (10, 39, 47).The results are diagrammedFigure 1). The surface is distinct amongleukocytes n manyespects and s consistent with their functional capaci-ties (see below), including antigen presentation (abundantsurfaceproducts), active clustering with T cells (high levels of several adhesins),and weakphagocytosis (low amountsof Fc and complement eceptors).Mostantigens are expressed in a homogeneousashion on dendritic cellsfromdifferent sites, but deviationscan occur. Thesemay epresent differ-ences expressed as dendritic cells mature and migrate from peripheraltissues to the T areas.Products of the MHCConsistent with their strong antigen-presenting cell function, dendriticcells express all class-ll MHCenes at high levels. Both I-A and I-E

MHCClass i q-t- Class II++

CD19-- 29-- 21 --22--40 +Ig -- 1[ CD16--32 + or-- 64 --23 +Tcell ~1~ /~ ~2Integrins

NK cell ~~ O~her receptorsCD56--57-- ~"/~~.j CD25CD35-MCSF-

Leukocyte commonantigenCD 45+45R~-

Foure 1.


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


9/28

DENDRITIC CELLS 279are abundant in the mouse, and HLA-DP,DQ, DR likewise in human.Monocytes ave low levels of DPand DQ 39). Dendritic cells have surfaceinvariant chain (CD74), as evidence by FACS 39) and precipitation~25I-labeled cells with polyclonal antibody (62).

Polymorphic class-I products also are abundant (39, 63-65) and canused to monitor the repopulation of dendritic cells in bone marrowchi-meras (66) or movementduring transplantation (22). Nonpolymorphicclass I (such as Qa and TI), which maypresent antigens to the ~/6 subset(68), have not been evaluated on dendritic cells. CD1, which s not encodedin the MHCut is class I-like and mayact as a restriction element for y/6T cells (69), is abundant on dendritic cells in skin (CDla) (4, 70)afferent lymph (CDlb) (38).Fc and C3 Receptors (FcR, C3R)Dendritic cells are not actively phagocytic. Consistent with this, there islittle or no expression of FcyR (CD16, CD32, CD64) or C3R (CDllb,CD21, CD35), as assessed by staining with mAbor binding of opsonizedparticles. Yet some exceptions are apparent. In skin, CD32 cTRare noted(1, 71, 72), but their levels fall by 90%when the Langerhans cells arecultured (8, 73, 74). Only freshly isolated Langerhans ells actively processandpresent native proteins (see below); this fact leads to the idea thatFc~Ron fresh Langerhanscells are involved in antigen uptake (75). Sheeplymph dendritic cells have cytophilic Ig and specific antibody enhancesantigen presentation (76).Fc~Rhave been studied on epidermal Langerhans cells. Binding of IgEis noted in situ in the skin of atopic patients (77), but the FceR-mediatingbind.ing has not been identified. Low-affinity FceRII (CD23)are upregu-lated with IL-4 and IFN-7 (78). Langerhans cells are implicated in thetransport of contact allergens as well (12, 79).C3bi (CD1 b) receptors typically are present at trace levels with theexception of mouseLangerhans cells where they are more readily detect-able (1).Other receptors used by phagocytes to scavenge particulates and micro-organisms have not been studied. Dendritic cells lack mannose-fucosereceptors (35), but no studies have been published on other receptors, e.g.for lipoproteins and scavenging. The lack of phagocytic receptors does notmean hat particulate antigens are not processed. It is possible these anti-gen-presenting cells take up small numbers f particles at defined stages oftheir natural history, or that particles are processedat the surface. Afferentlymphdendritic cells do not internalize test particles, yet someof the cellshave what appear to be phagocytic inclusions (35). The latter perhaps wereacquired in the tissues prior to entry into the lymph.


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


10/28

280 STEINMANIntegrins and AdhesinsThese molecules contribute to cell binding and homing,which are bothimportant eatures of dendritic cell function. Dendriticcells can havehighlevels of p150/90 r CD l c but lowCD~ 1 b (39, 49). CD 1 a or LFA-1found on dendritic cells in mouse pleen and human lood (39, 80) butnot skin (8, 73). Dendriticcells also have high levels of other adhesins,ICAM-1CD54),LFA-3 CD58),and fl~ integrin (CD29) 7,Differentiation AntigensMany roups are trying to prepare dendritic-cell specific mAb, ut thishas proven problematic. This is not for a lack of immunogenicity,incelarge numbers of mAb o shared markers are obtained following immu-nization with dendritic cells, e.g. mAbo MHCroducts and integrins(49). A groupof three mAbre useful in the mouse50). 33D1 eactsmostdendritic cells in spleen and Peyers patch, but not skin and thymicmedulla(10). NLDC145eacts with dendritic cells in skin and in thedependentregions of several lymphoidorgans, but also binds to thymicepithelium 48). N418 nti-CD1c reacts strongly with dendritic cells, butCD1 c can be upregulated on macrophages.Manymoleculesare expressed n a cell-type restricted fashion and areuseful for distinguishing dendritic cells. For example,dendritic cells inhuman lood (39) lack CD3 T cells), CD19-22 B cells), CD13-15the c-fms receptor for M-CSFphagocytes), and CD56/57 NKcells).Dendritic cells can express he B cell-activation markerCD407, 39, 40),and expression of CD4 nd CD8 lso occurs (10, 47). Some seful markersthat mouse endritic cells lack are CD45RA,hy-1, and certain phagocytemarkers hat lack a CDdesignation (SER-4,RB-6) 50).PRIMARY RESPONSES INDUCED BY DENDRITICCELLS: DISTINCT ANTIGEN-PRESENTING CELLREQUIREMENTS FOR THE AFFERENTAND EFFERENT LIMBS OF IMMUNITYThe erm "antigen-presenting ell" does not fully describe the function ofdendritic cells. Their distinctive role is to initiate T-dependentesponsesfrom quiescent lymphocytes.Once ensitized, the T lymphoblasts eadilyinteract with other antigen-presentingcells. In effect, efficient T-cellresponses both in vitro (81-83) and in vivo (84) seem to occur inphases. In the afferent limb, dendritic cells are specialized o identify andactivate trace clones of antigen-reactiveT cells while n the efferent limb,the sensitized blasts find other antigen-presenting ells to induceeffector


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


11/28

DENDRITIC CELLS 281functions such as macrophagectivation and IL-1 production, and B-cellantibody esponses. n this section, several primary esponses re reviewed,while in the next, aspects of mechanismre considered.The Primary Antibody ResponseTheneed for spleen adherent cells in the primaryantibody response by Band T lymphocytes85) led to the discoveryof dendritic cells whichprovedto be essential accessories (86). When oreign red blood cells are theantigen, dendritic cells stimulate he production f helper factors bypassingthe need or intact T cells (87). For haptencarrier conjugates, he need ordendriticcells is to sensitize carrier-specificT cells which irectly interactwith hapten-specificB cells as antigen-presenting ells (82). TheB cellsbecomeesponsive o antigen-nonspecific ytokines, and this all occurs indiscrete aggregates f dendritic, B, andT cells (88, 89).Some ncertainty exists concerning he relative roles of dendritic cellsand B cells as antigen-presentingells for sensitizing helper cells in situ(90). The lymphnodes of mice that are treated with anti-# from birthcannot be primedwith proteins in adjuvant (91-94). The nodespresumablyare depleted of B cells and not dendritic cells. In contrast, in studies ofantigen-presentingells function or antibody esponses, here are in vitrodata that mouse pleen responses require dendritic cells (82, 88) andvivo findings hat B cells in chickensare not the initial antigen-presentingcells for responses o heterologoused cells (95). In a study where ntigen-pulsed antigen-presenting ells have beenused to induceantibody n situ,it has been found hat dendritic cells induce he formation f antiviral andantiidiotypic antibodies(96).Primary Responses to Protein Antigens In SituIf spleendendriticcells are exposedo proteinantigens n vitro and njectedinto the foot pads of mice, CD4T cells in the draining lymphnode aresensitized (97). Responsivenesseaksat day 5, wanes y day 9-12, andrapidly induced by rechallenge with antigen-pulseddendritic cells. Whenspleen cells, which are 60%B lymphocytes, re pulsed with antigen andthen comparedo dendritic cells, the spleencells are muchess efficient asantigen-presenting cells in vivo (97). 106 spleen cells (t he maimumthat can be given readily in one dose nto a foot pad) induceweak esponseswhereas2 105 dendritic cells are muchmoreactive. As such, spleen Bcells lack direct sensitizing function at least for bulk exogenousroteins.Peritoneal macrophagesre totally inactive as antigen-presenting ells inthis in vivo assay system.The njected dendritic cells do not simplycarry antigens to be presentedby host antigen-presenting cells. This can be shown y injecting pulsed,


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


12/28

282 SaEr~MAr~parentalstrain dendriticcells into F 1 recipients. TheT cells that are primedrespond o antigen in the context of MHClass-II products of the injecteddendritic cells (97). This is the first instance n which ntigen-pulsed nti-gen-presentingcells have primedT cells in an MHC-restrictedashion invivo.Viral AntigensThe standard assay for studying the generation of antiviral CTL s toprime a mouseby exposure to virus and induce CTL y rechallenge invitro. Dendritic cells from mice that have been infected with Moloneyleukemia irus are active antigen-presentingells for inducing irus-specificCTL98). Dendriticcells also present Sendai o virus-primed pleen(98).eachcase, dendritic cells are 30-100 imes moreactive than unfractionatedspleen.Macatonia t al found that dendritic cells serve as antigen-presentingcells for primary CTL esponses in the influenza system (99). A specialculture systemwasneeded.105 cells werecultured in 20 #1 drops that hungfromwells of inverted Terasaki plates, a systemwhichmay mprove aseousexchange.A puzzling feature is that high levels of CTL ctivity develop na primary ive-day culture. This implies that the frequencyof precursorsfor flu-specific CTLn naive mice is high. Hengel t al also noted thatdendritic cells induce he formationof CTLo herpes simplex n a primarysystem 100). Limiting dilution assays indicated that herpes-specific CTLprecursors represent 1 in 400 of nylonwoolpassed, spleen T cells.The Primary Mixed Leukocyte ReactionThestrong stimulating activity of dendritic cells in the primary mixedleukocyte eaction (MLR)s established (101). Small B cells and monocytestrigger little or no response rom esting CD4T cells (39) but do stimulateactivated T-cell blasts and T-cell clones (102, 103). Certain B blasts andmany -cell lines are in contrast capableof stimulating he mixedeukocytereaction(80).Several lymphokines orm whendendritic cells stimulate the mixedleukocyte reaction. IL-2 is noted on day 1 (81, 83, 104, 105) and otherfactors soon thereafter: IL-4, IFN-y, and T cell replacing factors forantibody responses (81, 104, 106). Detailed studies have not yet beenpublished hat compare endritic cells with other antigen-presenting ellsfor defined TH1 nd Tn2subsets.

Dendritic cells also stimulate an MLRrom CD8T cells, but higherantigen-presenting cell doses are needed(83, 105). Allospecific CTL redetected at day 4-5 using dendritic to T-cell ratios of 1 : 10 or 1 : 30. The


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


13/28

DENDRITIC CELLS 283need or relatively high dosesof dendritic cells couldmeanhat the antigen-presenting cells are killed during the course of the response. TheCD8mixed eukocyte eaction is sizeable, with 30-40% f the culture at day 5being T blasts that express CD25 nd MHClass-II activation antigens.Monocyteso not stimulate resting CD8cells but serve as targets in theefferent limbof the response, .e. for the CTLhat are induced y dendriticcells.As few as 1 allogeneic dendritic cell per 100 CD4- esponders alsoinduces strong NK ctivity (K562 argets) (105). Theprecursors to theseNK ells can be removed electively prior to the MLRy panning theCD4-population with a-CD1 b mAb 105). That NKand allospecificCD8cells are induced n the absence of CD4helpers indicates that IL-2 and perhaps other cytokines can be generated in substantial amountsnthe cultures.COMPONENTSOF DENDRITIC CELL FUNCTION--MECHANISMS OF IMMUNOGENICITYBecause endritic cells induceprimary esponses n vitro and in vivo, theyare important for studying immunogenicityn a physiologic context. Thelimitation is that only small numbers f dendritic cells are available fromany tissue, and no cell lines exist. Yet dendritic cell numbers re largerelative to their specialized ask, i.e. to identify and activate he verysmallnumbers f antigen-specific T cells that are present at the onset of animmuneesponse.Todescribe these specializations, I do not use the "signal1/signal 2" terminology, ince the notion of two signals oversimplifies hemany eatures that contribute to dendritic cell function and does notconsider he distinct physiologic roperties of different antigen-presentingcells. Dendriticcell functioncan be consideredn three parts.Sentinel Function--Processin# nd Presentation of AntigenSUMMARY F RECENT ANTIGEN-PULSING EXPERIMENTS If pulsed with rela-tively low doses of soluble protein (100 #g/ml), dendritic cells stimulateantigen-specific, primedT cells (62, 97). Chloroquine locks pulsing (62)as it does n other types of antigen-presentingells (107, 108), implyingneed for an acidic intracellular compartment. everalfeatures of antigen-pulsed dendritic cells are apparent:1. Thenumber f pulsed dendritic cells needed o stimulate T cells islow, about 30-100 imes less than for mouse pleen (62, 75, 97), a standardantigen-presenting cell population which contains about 1%dendriticcells.


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


14/28

284 STEINMAN2. Antigen-pulsed dendritic cells, cultured for 1-2 days without further

exposure o antigen, retain activity (62, 97). This could mean hat the levelsof MHC-peptide omplexes are high, the turnover of complexes is slow,or that fewer complexesare needed for presentation by dendritic cells. Incontrast, if macrophages are pulsed, the turnover is rapid; the t~/2 ofpresenting activity is a few hours (109).

3. Antigen-pulseddendritic cells, but not other antigen-presenting cells,can be administered in situ to prime T cells without additional adjuvants(97). Priming s restricted to the draining lymphoid issue and is direct.F 1 T cells are primedwith parental dendritic cells, sensitization is restrictedto the MHCf the parental antigen-presenting cells.4. The processing activity of dendritic cells is regulated. Only freshisolates from epidermis (62, 75) and spleen (97) present native proteins.After a day in culture, the dendritic cells handle proteins poorly but arethe most potent antigen-presenting cells for stimuli that do not requireprocessing, e.g. peptides, alloMHC,and mitogens.

5. It is not yet possible to detect regurgitation of peptides processed byother antigen-presenting cells onto dendritic cells. Such experiments arepossible with cultured dendritic cells which can present pcptides but notproteins. If MHC-mismatchedpleen or peritoneal macrophages (97)Ia- epidermalcells (62) are mixedwith protein plus cultured dendritic cells,antigen-presenting cell function does not occur. If other cells regurgitateimmunogenic eptides, one would expect the dendritic cells to have stimu-lated the T cells.MECHANISMS OF ANTIGEN PROCESSING IN DENDRITIC CELLS Several vari-ables are being analyzed to explain the differences between fresh andcultured dendritic cells (see above). Both have high levels of surface MHCclass-II products, with cultured Langerhanscells expressing at least fivetimes more class II than fresh Langerhans cells (9, 110). When hodamine-ovalbumin is used to monitor endocytosis, fresh and cultured Langerhanscells internalize protein into intracellular granules (62). However,t is notyet possible to rigorously quantitate endocytic activity in fresh and culturedLangerhanscells, since these antigen-presenting cells are so weak. Stosselet al recently made he fascinating observation that freshly isolated Lan-gerhans cells have more numerousacidic vacuoles, presumably endosomes,whereas cultured mouse and humanepidermal Langerhans cells have someacidic lysosomesbut few acidic endocytic vesicles (111).

Pure et al have identified two more striking differences between freshand cultured Langerhans cells (62). Fresh Langerhans cells actively syn-thesize class-II products, while cultured Langerhans ells synthesize otherproteins but not class II. By blocking synthesis with cycloheximide, the


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


15/28

DENDRITIC CELLS 285efficiency with whichLangerhans ells can be pulsed with protein antigenis reduced. In addition, fresh but not cultured Langerhans ells expresshigh levels of cytoplasmicnvariant chain. The atter enhances resentationby cell lines transfected with MHClass-II genes(112). Thedata suggestthat the efficient processingof native proteins by fresh Langerhansells islinked to the synthesis of MHClass-II products. Perhaps newly syn-thesized molecules,associated with invariant chains, are shuttled to anacidic compartment here here is ready access to peptide antigens.Theability to downregulatehe presentation pathway, ncluding a down-regulation of class-II biosynthesis and a loss of invariant chains, is ofuncertain consequencet this time. Antigen-pulsed endritic cells retainantigen for long periods in an immunogenicorm (see above). Perhapsacquiredpeptides would e displaced f antigen processingwere o continuein an unregulated fashion. Continued ntigen processing, whendendriticcells are migrating from nonlymphoidissues to lymphoidT areas, alsowouldallow self-peptides to predominateover exogenous nes, and mightlead to autoimmunitysee Discussion).Althoughendritic cells can capture protein antigens, it is striking thatthe absolute amount f protein that accumulatesntracellularly is small(97). This suggests that while endocytic activity generates MHC-peptidecomplexes, he relevant levels of processing and presentation are smallespecially when omparedo the size and activity of the vacuolar systemthat is used to scavengeand degrade antigens in macrophages.Onemustdistinguish between ndocytosis hat is primarily directed towardantigenscavenging, the hallmark of the macrophage, nd the much ower amountsthat are associated with antigen-presenting ells function in dendritic andB cells. It has been knownor some ime that macrophagesnternalize andcompletely egrade t least 10,000protein molecules er hour at the dosesof protein that are used traditionally to pulse antigen-presenting ells.This scavenging unction makes ndocytosis, but not necessarily antigenprocessing, easy to visualize in macrophages113).CAPTUREFANTIGENSN SITUWhen ntigens are administered in situ,the dendritic cells can be isolated and showno be carrying the antigen inan immunogenicorm. This is tested by adding in vivo pulsed dendriticcells to specific T cells. T-cell stimulationoccurswith lungdendritic cellsafter aerosol administration of proteins (24), with afferent lymph heepdendritic cells after intradermal dministration f protein (38), with drain-ing lymph odedendritic cells after application of a contact allergen (14),and with thymic endritic cells after an i.v. bolus of protein (58). If miceare given oreignproteins .v. or i.p., dendriticcells seem o be the principalsource of immunogenelative to other cell types (53). The atter experi-


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


16/28

286 STEINMANmerits used selective depletion of in vivo pulsed antigen-presenting cellswith 33D1anti-dendritic cell mAb nd complement, as well as positiveselection with N418 anti-CD1 lc mAb nd the FACS 47).THE LEVELS OF ANTIGEN/MHC ON THE DENDRITIC CELL SURFACE The highlevels ofclass-I and -II MHC olecules on dendritic cells could function tocarry many ifferent epitopes, as in the presentation of complex nfectiousagents or foreign cells, and/or to accumulate large numbersof individualkinds of MHC-peptide omplexes to better identify and stimulate restingT cells. It is not yet possible to enumeratespecific MHC-peptideomplexeson dendritic cells. However,Romani t al (73) studied the numberofT cellsthat bind and respond to presentation of anti-CD3 on defined numbers ofLangerhans cells. As few as 250 FcR per Langerhans cell are needed todrive a T cell into cell cycle, and each Langerhans ell on average handles10-20 T cells.Migratory Functions-- the Binding of Antigen-SpecificT CellsMIGRATIONTO T-DEPENDENTAREAS AS detailed above, dendritic cells canmigrate via blood or afferent lymph to the T areas of spleen and lymphnode respectively. This places the antigen-charged dendritic cell in the pathof recirculating T cells, enhancing the chance that relevant T-cell clonescan be selected.The factors that stimulate and direct the movement f dendritic cells invivo are not clear. Simply grafting skin to isogeneic hosts or placing skinin organ culture induces egress of at least two thirds of the epidermalLangerhanscells (l 5). This suggests that movements T cell independent.However,homingmaybe T dependent since dendritic cells are not retainedin the spleens of nude mice (44). Dendritic cells express molecules that areimplicated in leukocyte homing, e.g. f12 integrins and CD44.The migratory properties of dendritic cells do not preclude a role instimulating immunity locally. This may occur in secondary responses,where dendritic cells are found in association with T cells at delayed typehypersensitivity sites (16). However, n certain primary responses, likesensitization to skin transplants (114) and contact allergens (115), afferentlymphatics need to be intact--a point consistent with the idea that a fluxof dendritic cells is critical to immunogenicity.CLUSTERING OF ANTIGEN-SPECIFIC T CELLS A feature that helps explaindendritic cell function is the capacity to form stable clusters with antigen-specific T cells during primary responses. Other antigen-presenting cellsdo not aggregate resting T cells but do bind sensitized T blasts (81, 82,103, 116).


Annu.R

ev.Immunol.1991.9:271-296.D

ownloadedfromarjournals.annu

alreviews.org

byRockefellerUniversityon08/15/07.Forpersonaluseonly

.


17/28

DENDRITIC CELLS 287In the living state, thin sheets or lamellipodia extend from the dendriticcell body in manydirections (33, 39, 117). The processes extend, retract,and bend as if the antigen-presenting cells are probing the environment

around them. This motility, which is distinct amongwhite cells, likelyenables the dendritic cell to survey T cells and select antigen-specific ones.Twoexamples indicate that the initial T-cell sampling occurs by anantigen-independent mechanism. irst, dendritic cells bind to T blasts thatare directed to specificities different from that present on the antigen-presenting cells (116). Second, whencultured in close proximity, dendriticcells bind resting T cells in large numbers, oo many or all to be antigen-specific (118). In both instances, boundT cells do not produce IL-2 unlessanother stimulus like a mitogen is added. Antigen-independent bindingcould provide a temporary state of antigen-presenting cell T-cell contact,which may be essential for the appropriate TCR-antigen-MHCnteractionto occur.The molecules that mediate antigen-independent clustering have yet tobe identified. As mentioned, adhesins like ICAM-1 nd LFA-3are abun-dant on dendritic cells (39, 119). To date, mAb o//2 integrins have notblocked heterotypic clustering with T cells in the mixed eukocyte reaction(49, 80, 120), although ~-CD18mAbdoes block when the stimulussodium periodate (121). Other adhesins are under study, including CD2and CD28.Adjuvant Function-- T-Cell ActivationIL-I ANDDENDRITICELL UNCTIONor years the main hypothesis for themechanism of T-cell activation has been that macrophage-derivcd IL-1induces IL-2 release or responsiveness. Dendritic cells and B cells are activeantigen-presenting cells but are not known o make L-1 (122-125), exceptfor a report of IL-1 in freshly isolated epidermal Langerhanscells (126).It remains to be shown that a response of primary T cells, rather thanchronically stimulated cell lines, can be blocked with antibodies to IL-1 orIL-1 receptors. For example, T lymphoblasts can engage macrophagesand induce IL-1 production (102, 103), but the T-cell proliferation thatoccurs in these cultures is insensitive to neutralizing anti-IL-1 (103).Attempts have been made o identify other activating factors that mightbe produced under dendritic cell control. These have yet to be found.Inaba et al placed dendritic-T-cell clusters on one side of a millipore filter,and T cells exposed to u-CD3on the other side. IL-2 was produced by theclusters and crossed the filter, but no activation occurred even though theTCRcomplex was occupied by ~-CD3 118). This suggests that the signalsprovided by dendritic cells for T-cell activation are either active over shortdistances or remain membranebound.


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


18/28

288 STEINMANCYTOKINES AMPLIFY THE FUNCTION OF DENDRITIC CELLS While cytokineproduction by dendritic cells is not yet well documented, cytokines canenhance T cell-mediated immunity by amplifying the viability and functionof these antigen-presenting cells. Interestingly, each active cytokine hasdistinct effects. Cachectin-TNFmaintains Langerhans cell viability butdoes not enhance sensitizing function (6). IL-l enhances the functionskin, spleen, and thymic dendritic cells but does not increase viability (3,51,127). GM-CSFnhances both viability and function (2, 3, 52, 128).As yet no cytokine has been identified that upregulates the level ofdendritic cell MHC roducts. Lymphokines ike IFN-~ and IL-4 induceclass-II products on macrophages and B cells, respectively, but do notsimilarly increase expression on dendritic cells.

Specific cytokine receptors have not been identified on dendritic cellsexcept for the low affinity, p55, IL-2 receptor chain (CD25),first detectedon mouseepidermal Langerhans cells (129). CD25has since been founddendritic cells from manysites--mouse spleen (10), rat afferent lymph(52), human lood (39)--but the function on these antigen-presenting cellsis not known.

By influencing dendritic cell function, cytokines mayplay a pivotal rolein immunogenicity, e.g. in skin, GM-CSFelease by keratinocytes (2) maymobilize stimulatory dendritic cells. The phenotype of dendritic cells inblood, lymph, and lymphoidorgans is that of a cell that has been activatedby cytokines, since leukocytes commonly upregulate MHC roducts,adhesins, and IL-2 receptors upon activation. All of these molecules areexpressed at high levcls on dendritic cells (see above).SURFACE MOLECULES CONTRIBUTING TO DENDRITIC CELL FUNCTION Manyligand receptor systems, such as LFA-1/ICAM nd LFA-3/CD2may con-tribute both to cell-cell adhesion and to signalling (130). Studies are under-way o test the effects ofmAbo these molecules on dendritic cell function,particularly in clusters of antigen-presenting cells and T cells that are themicroenvironment for manyresponses in vitro. Because of the difficultyencountered in identifying secreted lymphocyteactivating factors (above),it is important to search for specific dendritic cell surface molecules thatcontribute to T-cell signalling. However,t is possible that dendritic cellsuse surface signalling molecules that can be expressed by manycell types,such as LFA-3 and ICAM-1, but that the key feature of these antigen-presenting cells is the capacity to upregulate manyadhesion/signallingsystems in a T-independent ashion at the site of antigen deposition. Recentstudies of humanLangerhans cells indicate that dendritic cells rapidlyupregulate adhesion molecules in vitro, in the apparent absence of T cells(7, 8). These maturation events, coupled with the other specializations (see


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


19/28

DENDRITIC CELLS 289above) in antigen handling and migration, help explain the immuno-genicity of antigen-pulsed dendritic cells.CLONALXPANSIONF T CELLSFor many mitogens, such as lectins andanti-CD3 mAb, the accessory function of macrophages compares withthat of dendritic cells. Mitogens maymediate macrophage-T ell cluster-ing, which is not observed in primary antigen-specific responses. However,the T-cell function being measured is the onset of DNA ynthesis, notlong-term clonal expansion. When ntigen-presenting cell requirementsfor the latter were addressed (131), dendritic cells proved to be remarkablymore efficient than other antigen-presenting cells. A thousand dendriticcells mediate the optimal cloning efficiency of single T cells in the presenceof lectin and exogenous L-2. Some lones develop with just one dendriticcell, while few clones develop with up to 104 monocytes. n effect, dendriticcells are able to induce long-term T-cell responsiveness to growth factorslike IL-2.Using dendritic cells as immunoadsorbents, ancholi et al cloned T cellsthat had been bound in clusters (132). Macrophages had to be removedto enhance cluster formation. Antigen was needed to select but not expandthe clones. These findings, plus those showing antigen capture in vivo,suggest a use for dendritic cells to select clones that are specific for physio-logically relevant antigens on antigen-presenting cells in vivo.

DISCUSSIONThis review has emphasized dendritic cells and immunogenicity. Theseantigen-presenting cells are in essence natures adjuvant and allow one tostudy responses to specific antigens both in tissue culture and in wholeanimal models. The data discussed above on distinct antigen handlingfunctions, the lack of IL-1 production, the ability to migrate and formstable contacts with T cells, the afferent and efferent limbs of antigen-presenting cells function, all have become pparent via direct analyses ofthis trace but specialized subset of antigen-presenting cells.Given their role in presentation of antigens on self and allogeneic MHCmolecules, t will be important to test the contribution of dendritic cells toself-tolerance. Metzinger & Guerder found that dendritic cells tolerizedcells in organ cultures of fetal mouse hymus (133). Inaba et al obtaineddata in an Mls system that neonatal tolerance can be induced with dendriticcells, but it is the result of clonal anergy not deletion (134). FairchildAustyn workedout methods for placing dendritic cells within the medullaof thymic organ cultures (135); these methods should be useful for future


Annu.R

ev.

Immunol.1991.9:271-296.D

ownloadedfroma



08/15/07.

Forpersonaluseonly.


20/28

290 STEINMANstudies. The capacity of dendritic cells to induce suppressor cells againstself-reactivity has not been ested.Given the likelihood that manyself-reactive T cells are not tolerized(136), one must consider that the avoidance of self can also reflect theextent to which a given protein is captured and presented by dendriticcells, and the extent to which dendritic cells are activated and mobilizedby cytokines or other factors. In other words, tolerance in the adultoperates not only at the level of the T cell but also at the level of thedendritic cell. For manyantigens, the distinction is not between foreignand self, but in the extent to which a given protein, foreign or self, iscaptured and presented by stimulatory dendritic cells.ACKNOWLEDGMENTSThis work has been supported by grants AI13013, AI24540, and AI24775from the National Institutes of Health.

Literature Cited1. Schuler, G., Steinman, R. M. 1985.Murine epidermal Langerhans cellsmature into potent immunostimu-latory dendritic cells in vitro. J. Exp.

Med. 161:526-462. Witmer-Pack, M. D., Olivier, W.,Valinsky, J., Schuler, G., Steinman, R.M. 1987. Granulocyte/macrophagecolony-stimulating factor is essentialfor the viability and function of cul-tured murine epidermal Langerhansceils. J. Exp. Med. 166:1484-983. Heufler, C., Koch, F., Schuler, G. 1987.Granulocyte-macrophage colony-stim-ulating factor and interleukin-1mediate the maturation of murine epi-dermal Langerhans cells into potentimmunostimulatorydendritic cells. J.Exp. Med. 167:700-54. Fithian, E., Kung, P., Goldstein, G.,Rubenfeld, M., Fenoglio, C., Edelson,R. 1988. Reactivity of Langerhanscellswith hybridoma antibody. Proc. Natl.Acad. Sci. USA 78:2541445. Romani, N., Witmer-Pack, M., Crow-ley, M., Koide, S., Schuler, G., Inaba,K., Steinman, R. M. 1990. Langcrhanscells as immature dendritic cells. InEpidermal Langerhans Cells. CRC6. Koch, F., Heufler, C., K/impgen, E.,Schneeweiss, D., B6ck, G., Schuler. G.1990. Tumor necrosis factor alphamaintains the viability of routine epi-dermal Langerhans cells in culture butin contrast to granulocyte/macrophage

colony-stimulating factor, does notinduce their functional maturation. J.Exp. Med. 171:159-727. Romani,N., Lenz, A., Glassl, H., Stos-sel, H., Stanzl, U., Majdlc, O., Fritsch,P., Schuler, G. 1989. Cultured humanLangerhans cells resemble lymphoiddendritic cells in phenotype and func-tion. J. Invest. DermatoL 3:600-98. Teunissen, M. B. M., Wormmeester, .,Krieg, S. R., Peters, P. J., Vogels, I. M.C., Kapsenberg,M. L., Bos, J. D. 1990.Human epidermal Langerhans cellsundergo profound morphologic andphenotypical changes during in vitroculture. J. Invest. Dermatol. 94:166-739. Witmer-Pack, M. D., Valinsky, J.,Olivier, W., Steinman, R. M. 1988.Quantitation of surface antigens oncultured murine epidermal Langerhansceils: rapid and selective increase in thelevel of surface MHC roducts. J.Invest. Dermatol. 90:387-9410. Crowley, M., lnaba, K., Witmer-Pack,M., Steinman, R. M. 1989. The cellsurface of mouse dendritic cells: FACSanalyses of dendritic cells from differ-ent tissues including thymus. Cell.Immunol. 118:108-25I1. Kelly, R. H., Balfour, B. M.,Armstrong, J. A., Griffiths, S. 1978.Functional anatomy of lymph nodes.II. Peripheral lymph-borne mono-nuclear cells. Anat. Rec. 190:5-2112. Silberberg-Sinakin, I., Thorbecke, G.


Annu.Rev.Immunol.1991.9:271-296.D

ownloadedfromarjournals.annu

alreviews.org

byRockefellerUniversityo

n08/15/07.Forpersonaluseonly

.


21/28

J., Baer, R. L., Rosenthal, S. A., Bere-zowsky, V. 1976. Antigen-bearing Lan-gerhans cells in skin, dermal lymphaticsand in lymph nodes. Cell. ImmunoL 5:137-5113. Hoefsmit, E. C. M., Duijvestijn, A. M.,Kamperdijk, W. A. 1982. Relationbetween Langerhanscells, veiled cells,and interdigitating cells. Immuno-biology 161:255 6514. Macatonia, S. E., Knight, S. C.,Edwards,A. J., Griffiths, S., Fryer, P.1987. Localization of antigen on lymphnode dendritic cells after exposure tothe contact sensitizer fluorescein iso-thiocyanate. J. Exp. Med. 166: 1653-6715. Larsen, C. P., Steinman, R. M., Wit-mer-Pack, M. D., Hankins, D. F., Mor-ris, P. J., Austyn, J. M. 1990. Migrationand maturation of Langerhans cells inskin transplants and explants. J. Exp.Med. 172:1483-9416. Kaplan, G., Nusrat, A., Witmer, M.D., Nath, I., Cohn, Z. A. 1987. Dis-tribution and turnover of Langerhanscells during delayed immune esponsesin human kin. J. Exp. Med. 165:7637617. Hart, D.N.J.,Fabre, J.W. 1981.Dem-onstration and characterization of la-positive dendritic cells in the interstitialconnective tissues of rat heart and othertissues, but not brain. J. Exp. Med.154:347-6118. Prickett, T. C. R., McKenzie, J, L.,Hart, D. N. J. 1988. Characterizationof interstitial dendritic cells in humanliver. TransplantationA,6:754-6119. Hart, D. N. J., McKenzie, J. L. 1990.Interstitial dendritic cells. Int. Rev.Immunol. 6:128-4920. Spencer, S. C., Fabre, J. W. 1990. Char-acterization of the tissue macrophageand the interstitial dendritic cell as dis-tinct leukocytes normally resident inthe connective tissue of rat heart. J.Exp. Med. 171:1841-5121. Larsen, C. P., Morris, P. J., Austyn, J.M. 1990. Migration of dendritic leu-kocytes from cardiac allografts intohost spleens: a novel pathway forinitiation of rejection. J. Exp. Med.171:307-1422. Codner, M. A., Shuster, B. A., Stein-man, R. M., Harper, A. D., LaTrenta,G. S., Hoffman, L. A. 1990. Migrationof donor leukocytes from limb allo-grafts i~ato host lymphoid issues. Ann.Plastic Surg. 25:353-5923. Klinkert, W. E. F., Labadie, J. H.,Bowers, W. E. 1982. Accessory and stim-ulating properties of dendritic cells and

DENDRITIC CELLS 291macrophages isolated from various rattissues- J. Exp. Med.156; 1-1924. Holt, P. G., Schon-I-Iegrad, M. A.,Ofiver, J. 1987. MHClass II antigen-bearing dendritic cells in pulmonaryis-sues of the rat. Regulation of antigenpresentation activity by endogenousmacrophage populations. J. Exp. Med.167:26~7425. Rochester, C. L., Goodell, E. M., Stoptent~org, J. K., Bowers, W. E. 1988.Dendritic cells from rat lung are potentaccessory cells. Am. Rev. Respir. Dis.138:121-2826. Sertl, K., Takemura, ., Tschachler, E.,Ferrans, V. J., Kaliner, M.A., Shevach,E. M. 1986. Dendritic cells with anti-gen-presenting capability reside in air-way epithelium, lung parenchyma, andvisceral pleura. J. Exp. Med.163: 436-5127. Pollard, A. M., Lipscomb, M. F. 1990.Characterization of murlne lung den-dritic cells: Similarities to Langerhanscells and thymicdendritic cells. J. Exp.Med. 172:159-6828. Nicb.od, L. P., Lipscomb, M. F.,Weissler, J. C., Lyons, C. R., Alberton,J., Toews, G. B. 1987. Mononuclearcells in human ung parenchyma: char-acterization of a potent accessory cellnot obtained by bronchoalveolarlavage. Am. Rev. Respir. Dis. 136: 818-2329. Nicod, L. P., Lipscomb, M. F.,Weissler, J. C., Toews, G. B. 1989.Mononuclear cells from human lungparenchy~na support antigen-inducedT lymphocyte proliferation. J. Leuk.Biol. 45: 336~A30, Holt, P. G., Schon-Hegrad, M. A,,MeMenarnin, P. G. 1990. Dendriticcells in the respiratory tract. Int. Rev.Immunol. 6:139-4931. Pavli, P., Woodhams,C. E., Doe, W.F., Hume, D. A. 1990, Isolation andcharacterization of antigen-presentingdendritic cells from the mouse intes-tinal lamina propria. Immunology70:4O-4732. Knight, S. C., Balfour, B. M., OBrien,J., Buttifant, L., Sumerska, ., Clark, J.1982. Role of veiled cells in lymphocyteactivation. Eur, J. Immunol.12: 105%6O33. Drexhage, H. A., Mullink, H., deGrout, J., Clarke, J., Balfour, B, M.1979. A study of cells present in pe-ripheral lymphof pigs with special ref-erence to a type of cell resembling theLangerhans cells. Cell Tiss. Res. 202:4O7-3034. Mason, D. W., Pugh, C. W., Webb, M.


Annu.

Rev.

Immunol.1991.9:271-296.

Do

wnloadedfroma

rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


22/28

292 STEINMAN1981. The rat mixed lymphocyte reac-tion: roles of a dendritic cell in intes-tinal lymphand T cell subsets definedby monoclonal antibodies. Immu-nology 44:75-8735. Pugh, C. W., MacPherson, G. G,Steer, H. W. 1983. Characterization ofnonlymphoid cells derived from ratperipheral lymph. J. Exp. Med. 157:1758 7936. Rhodes, J. M., Agger, R. 1987. Com-parison of membrane antigens ofmouse dendritic cell types. Immunol.Lett. 16:107-1237. Spry, C. J. F., Pflug, A. J., Janossy, G.,Humphrey, J. H. 1980. Large mono-nuclear (veiled) cells with "Ia-like"membrane antigens in human afferentlymph. Clin. Exp. Immunol. 39:750

38. Bujdoso, R., Hopkins, J., Dutia, B. M.,Young, P., McConnell, I. 1989. Char-acterization of sheep afferent lymphdendritic cells and their role in antigencarriage. J. Exp. Med. 170:1285-130239. Freudenthal, P., Steinman, R. M. 1990.Surface antigens and motility of humandendritic cells enriched from blood byan improved technique. Proc. Natl.Acad. Sci. USA.In press40. Hart, D. N., McKenzie, . L. 1988. Iso-lation and characterization of humantonsil dendritic cells. J. Exp. Med.168:157 7041. Veldman, J. E., Kaiserling, E. 1980.Interdigitating cells. In The Reticulo-endothelial System, Morphology,editedby I. Carr and W. T. Daems, p. 381-416. New York: Plenum42. Witmer, M. D., Steinman, R. M. 1984.The anatomy of peripheral lymphoidorgans with emphasis on accessorycells: light microscopic, immuno-cytochemical studies of mouse spleen,lymph node and Peyers patch. Am.J. Anat. 170:465-81

43. Dijkstra, C. D. 1982. Characteriza-tion of nonlymphoidells in rat spleen,with special reference to strongly Ia-positive branchedcells in T-cell areas.J. Reticuloendothelial Soc. 32:167-7844. Austyn, J. M., Kupiec-Weglinski, J.W., Hankins, D. F., Morris, P. J. 1988.Migrationpatterns of dendritic cells inthe mouse. Homingo T cell-dependentareas of spleen, and binding withinmarginal zone. Z Exp. Med. 167: 646-5145. Fossum, S. 1989. Lymph-borne den-dritic leukocytes do not recirculate, butenter the lymph node paracortex tobecome nterdigitating cells. Scand. J.Immunol. 27:97-10546. Steinman, R. M., Lustig, D. S., Cohn,

Z, A. 1974.Identification of a novel celltype in peripheral lymphoid organs ofmice. III. Functional properties in vivo.J. Exp. Med. 139:14314547. Crowley, M. T., Inaba, K., Witmer-Pack, M. D., Gezelter, S., Steinman,R. M. 1990. Use of the fluorescenceactivated cell sorter to enrich dendriticcells from mouse spleen. J. Immunol.Methods. In press48. Kraal, G,, Breel, M., Janse, M., Bruin,G. 1986. Langerhans ells, veiled cells,and interdigitating cells in the mouserecognized by a monoelonal antibody.J. Exp. Med. 163:981-9749. Metlay, J. P., Witmer-Pack, M. D.,Agger, R., Crowley, M. T., Lawless,D., Steinman, R. M. 1990. The distinctleukocyte integrins of mouse spleen

dendritic cells as identified with newhamster monoclonal antibodies. J.Exp. Med. 171:1753-7250. Agger, R., Crowley, M. T., Witmer-Pack, M. D. 1990. The surface of den-dritic cells in the mouseas studied withmonoclonal antibodies. Int. Rev.Immtmol. 6:89-10151. Koide, S. L., Inaba, K., Steinman, R.M. 1987. Interleukin-1 enhances T-dependent immune esponses by ampli-fying the function of dendritic cells. J.Exp. Med. 165:515 3052. MacPherson, G. G., Fossum, S., Har-rison, B. 1989. Properties of lymph-borne (veiled) dendritic cells in cultureII. Expressionof the IL-2 receptor: roleof GM-CSF. Immunology 68:108 1353. Crowley, M., Inaba, K., Steinman, R.M. 1990. Dendritic cells are the prin-cipal cell in mouse spleen bearingimmunogenic ragments of foreign pro-teins. J. Exp. Med. 172:383-8654. Barclay, A. N., Mayrhofer, G. 1981.Bone marroworigin of Ia-positive cellsin the medulla of rat thymus. J. Exp.

Med. 153:1666-7155. Guillemot, F. P., Oliver, P. D., Peault,B. M., LeDourain, N. M. 1984. Cellsexpressing Ia antigen in the avianthymus. J. Exp. Med. 160:1803-1956. Kaiserling, E., Stein, H., Mueller-Her-melink, H. K. 1974. Interdigitatingreticulum cells in the human hymus.Cell Tiss. Res. 155:4~5557. Duijvestijn, A. M., Schutte, R., Kohler,Y. G., Korn, C., Hoefsmit, E. C. M.1983. Characterization of the popu-lation of phagocytic cells in thymiccellsuspensions. A morphological andcytochemical study. Cell Tiss. Res. 231:313-2358. Kyewski, B. A., Fathman, C. G.,Rouse, R. V. 1986. Intrathymic pres-


Annu.

Rev.

Immunol.1991.9:271-296.

Do

wnloadedfroma

rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


23/28

entation of circulating non-MHCnti-gens by medullary dendritic cells. Anantigen-dependent microenvironmentfor T cell differentiation. J. Exp. Med.163:231~,659. 0liver, P. D., Le Dourain, N. M. 1984.Avian thymic accessory cells. J. Immu-nol. 132:1748-5560. Fossum, S. 1989. The life history ofdendritic leukocytes [DL]. In CurrentTopics in Pathology, O. H. Ivessen, pp.101-24. Berlin: Springer-Verlag61. Katz, S. I., Tamaki, K., Sachs, D. H.1979. Epidermal Langerhans cells arederived from cells originating in bonemarrow. Nature 282:324-2662. Pure, E., Inaba, K., Crowley, M. T.,Tardelli, L., Witmer-Pack, M. D.,Ruberti, G., Fathman, G., Steinman,R. M. 1990. Antigen processing by epi-dermal Langerhanscells correlates withthe level of biosynthesis of MHClassII molecules and expression ofinvariant chain. J. Exp. Med.172:145963. Boog, C. J. P., Boes, J., Melief, C. J.M. 1988. Role of dendritic cells in theregulation of class I restricted cytotoxicT lymphocyte responses. J. Immunol.140:3331-3764. Nussenzweig, M. C., Steinman, R. M.,Unkeless, J. C., Witmer, M. D., Gut-chinov, B., Cohn, Z. A. 1981. Studiesof the cell surface of mouse dendriticcells and other leukocytes. J. Exp. Med.154:168-8765. Steinman, R. M., Kaplan, G., Witmer,M. D., Cohn, Z. A. 1979. Identificationof a novel cell-type in peripheral lymph-oid organs of mice. V. Purification ofspleen dendritic cells, newsurface mar-kers, and maintenance n vitro. J. Exp.Med. 149:1-1666. Lenz, A., Heufler, C., Rammensee,H.-G., Glassl, H., Koch, F., Romani, N.,Schuler, G. 1989. Murine epidermalLangerhans cells express significantamounts of class I major histo-compatibility complex antigens. Proc.Natl. Acad. Sci. USA86:7527-3167. Suthanthiran, M. 1990. A novel modelfor antigen-dependent activation ofnormal human T cells. J. Exp. Med.171:1965-8068. Bonneville, M., Ishida, I., Itohara, S., Verbeek, S., Berns, A., Kanagawa, O.,Haas, W., Tonegawa,S. 1990. Self-tol-erance to transgenic gammadelta Tcells by intrathymic inactivation.Nature 344:163~5569. Porcelli, S., Brenner, M.B., Greenstein,J. L., Balk, S. P., Terhorst, C., Bleicher,P. A. 1989. Recognition of cluster ofdifferentiation I antigens by human

DENDRITIC CELLS 293CD4-CD8-cytolytic T lymphocytes.~Vature341: 44770. Ray, A., Schmitt, D., Dezutter-Dam-buyant, C., Fargier, M.-C., Thivolet, J.1989. Reappearance of CDla antigenicsites after endocytosis on humanLan-gerhans cells evidenced by immunogoldrelabeling. J. Invest. Dermatol.92:2172471. Tamaki, K., Stingl, G., Gullino, M.,Sachs, D. H., Katz, S. I. 1979. Ia anti-gens in mouse skin are predominantlyexpressed on Langerhans cells. J.Immunol. 123:784-8772. Haines, K. A., Flotte, T. J., Springer,T. A., Gigli, I., Thorbecke,13. J. 1983.Staining of Langerhans cells withmonoclonal antibodies to macrophagesand lymphoid cells. Proc. Natl. Acad.Sci. USA80:3448-5173. Romani, N., Inaba, K., Witmer-Pack,M., Crowley, M., Pure, E., Steinman,R. M. 1989. A small number of anti-CD3molecules on dendritic cells stimu-late DNA ynthesis in mouse T lym-phocytes. J. Exp. Med. 169:1153-6874. Schmitt, D. A., Hanau, D., Bieber, T.,Dezutter-Dambuyant, C., Schmitt, D.,Fabre, M., Pauly, G., Cazenave, J.-P.1990. Human epidermal Langerhanscells express only the 40-kilodalton Fcgamma eceptor [FcRII]. J. Imrnunol.144:4284-9075. Romani, N., Koide, S., Crowley, M.,Witmer-Pack, M., Livingstone, A. M.,Fathman, C. G., Inaba, K., Steinman,R. M. 1989. Presentation of exogenousprotein antigens by dendritic cells to Tcell clones: intact protein is presentedbest by immature, epidermal Lan-gerhans cells. J. Exp. Med. 169:1169-7876. Bujdoso, R., Harkiss, G., Hopkins, J.,McConnell, I. 1990. Afferent lymphdendritic cells: A model for antigencapture and presentation in vivo. Int.Rev. Immunol. 6:177-8677. Bieber, T., Dannenberg, B., Prinz, J.C., Rieber, E. P., Stolz, W., Braun-Falco, O., Ring, J. 1989. Occurrence ofIgE bearing epidermal Langerhans cellsin atopic eczema: A study of the timecourse of the lesions and with regard tothe IgE serum evel. J. Invest. Dermatol.93:215-1978. Bieber, T., Rieger, A., Neuchrist, C.,Prinz, J. C., Rieber, E. P., Boltz-Nitu-lescu, G., Scheiner, O., Kraft, D., Ring,J., Stingl, G. 1989. Induction ofFcR/CD23 on human epidermal Lan-gerhans cells by human recombinantinterleukin-4 and interferon-gamma. J.Exp. Med. 170:309-14


Annu.

Rev

.Immunol.1991.9:271-296.

Downloadedfroma


byRockefellerUniversityon08/15/07.

Forpersonaluseonly.


24/28

294 STEINMAN79. Shelley, W.B., Juhlin, L. 1976. Lan-gerhanscells form reticuloepithelialtrap for external contact allergens.Nature261 46-4780. Metlay,J. P., Pure, E., Steinman,R.M.1989.Distinct features of dendritic

cells and anti-immunoglobulin cti-vated B cells as stimulatorsof the pri-marymixedeukocytereaction. J. Exp.Med.169:239-5481. Inaba, K., Steinman,R. M. 1984.Rest-ing and sensitized T lymphocytesxhi-bit distinct stimulatory (antigen-pre-senting cell) requirements or growthand lymphokineelease. J. Exp. Med.160:1717-3582. Inaba, K., Steinman,R. M. 1985. Pro-tein-specific helper T lymphocyteor-mation nitiated bydendriticcells. Sci-ence 229:475-7983. Inaba, K., Young, . W., Steinman,R.M. 1987. Direct activation of CD8+cytotoxic T lymphocytes y dendriticcells. J. Exp. Med.166:182-9484. Inaba, K., Metlay, J. P., Crowley,M.T., Witmer-Pack,M., Steinman,R. M.1990. Dendritic cells as antigen pre-sentingcells in vivo.Int. Rev. lmmunol.6:197-20685. Mosier, D. E. 1967. A requirement ortwo cell types for antibody ormationin vitro. Science158:1573-7586. Inaba, K., Steinman, R. M., VanVoorhis, W. C., Muramatsu,S. 1983.Dendritic cells are critical accessorycells for thymus-dependent ntibodyresponses in mouse and man.Proc.Natl. Acad. Sci. USA80:6041-4587. Inaba, K., Granelli-Piperno,A., Stein-man,R. M.1983. Dendriticcells induceT lymphocyteso release B cell stimu-lating factors by an interleukin 2dependent mechanism.J. Exp. Med.158:2040-5788. Inaba, K., Witmer, M. D., Steinman,R. M. 1984. Clustering of dendriticcells, helper T lymphocytes,ndhisto-compatible B cells, during primaryantibody responses in vitro. J. Exp.Med.160:858-7689. Inaba, K., Steinman,R. M.1987. Den-dritic and Bcell functionduring anti-body responses in normal and immu-nodeficient xid) mousepleen cultures.Cell. lmrnunol.105:432-4290. Metlay, J. P., Pure, E., Steinman,R.M. 1989. Control of the immuneresponse at the level of antigen pre-sentingcells: a comparisonf the func-tion of dendritic cells and B lympho-cytes. Adv. Immunol.47:45-11691. Ron, Y., DeBaetselier,P., Gordon, .,Feldman,M., Segal, S. 1981.Defective

induction of antigen-reactive pro-liferating T cells in B cell-deprivedmice. Eur. J. Immunol. 1:964-6892. Janeway,C. A. Jr., Ron, J., Katz, M.E. 1987.TheB cell is the initiating anti-gen-presenting ell in peripheral lymphnodes. J. Immunol.138:1051-5593. Kurt-Jones, E. A., Llano, D., HayGlass, K. A., Benacerraf, B., Sy,M.-S., Abbas,A. K. 1988. Therole ofan.tigen-presen.ting Bcells in T cellpriming in vlvo. Studies of B cell-deficient mice. J. Immunol. 40: 3773-7694. Ron,Y., Sprent, J. 1989.T cell primingin vivo: a major ole for B cells in pre-senting antigen to T cells in lymphnodes. J. Imrnunol.138:2848-5695. Lassila, O., Vainio, O., Matzinger,P.1988.CanBcells turn on virgin T cells?Nature 334:253-5596. Francotte, M., Urbain, J. 1985.Enhancementf antibody responses bymouse dendritic cells pulsed withtobacco mosaic virus or with rabbitantiidiotypic antibodiesraised againsta private rabbit idiotype. Proc. Natl.Acad. Sci. USA82:8149-5297. Inaba, K., Metlay, J. P., Crowley,M.T., Steinman, R. M. 1990. Dendriticcells pulsed with protein antigens invitro can primeantigen-specific, MHCorestricted T cells in situ. J. Exp.Med.172:631-4098. Kast, W. M., Boog, C. J. P., Roep, B.O., Voordouw, . C., Melief, C. J. M.1988. Failure or success in the res-toration of virus-specific cytotoxic Tlymphocyte esponse defects of den-dritic cells. J. Immunol.40:3186-9399. Macatonia, S. E., Taylor, P. M.,Knight, S. D., Askonas,B. A. 1989.Primary timulation by dendritic cellsinduces anti-viral proliferative andcytotoxic T cell responses n vitro. J.Exp. Med.169:1255~54100. Hengel, H., Lindner, M., Wagner,H.,Heeg, K. 1987. Frequencyof herpessimplexvirus-specific murine ytotoxicT lymphocyteprecursors in mitogen-and antigen-driven primary in vitro Tcell responses,d. Immunol. 39: 4196-4202101. Steinman, R. M., Inaba, K. 1985.Stimulationof the primary mixed eu-kocyte reaction. CRC rit. Rev. Immu-nol. 5:331-48102. Koide, S., Steinman, R. M. 1988.Induction of interleukin 1 alphamRNAuring the antigen-dependentinteraction of sensitized T lym-phoblasts with macrophages.J. Exp.Med. 168:409-16


Annu.

Rev.

Immunol.1991.9:271-296.

Do

wnloadedfroma

rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


25/28

103.Bhardwaj, N., Lau, L. U, Friedman,S. M., Crow,M. K., Steinman, R. M.1989. Interleukin-1 productionduringaccessory cell-dependent mitogenesisof T lymphocytes.J. Exp. Med.169:1121-36104.Freudenthal, P., Bhardwaj,N. 1990.Dendritic cells in humanblood andsynovial exudates. Int. Rev. Immunol.6:103-116105.Young,J. W., Steinman, R. M. 1990.Dendritic cells stimulate primaryhuman ytolytic lymphocyte esponsesin the absenceof CD4+elper T cells.J. Exp. Med.171:1315-30106.Pure, E., Inaba, K., Metlay,J. 1988.Lymphokine roduction by murine Tcells in the mixedeukocyteeaction. J.Exp. Med.168:795-800107. Ziegler, H. K., Unanue,E. R. 1982.Decrease n macrophagentigen catab-olism caused by ammonia nd chloro-quine s associated with inhibition ofantigenpresentationT cells. Proc.Natl.Acad. Sei. USA79:175-78108. Lanzavecchia, A. 1985. Antigen-spe-cific interaction between andB cells.Nature 314:537-39109.Harding, C. V., Roof, R. W., Unanue,E. R. 1990. Turnover of Ia-peptidecomplexess facilitated in viable anti-gen-presentingells: Biosyntheticurn-

over of Ia vs. peptide exchange,Proc.Natl. Acad. Sei. USA86:4230-34110. Shimada, S., Caughman, . W., Shar-row, S. O., Stephany,D., Katz, S. I.1987. Enhancedantigen-presentingcapacity of cultured Langerhans ellsis associated with markedlyncreasedexpression of Ia antigen. J. Immunol.139:2551-55111. Sttssel, H., Koch, F., K~impgen, .,Sttger, P., Lenz, A., Heufler, C.,Romani,N., Schuler, G. 1990. Dis-appearance f certain acidic organelles[endosomes nd Langerhans ell gran-ules! accompaniesoss of antigen pro-cessing capacity uponculture of epi-dermalLangerhans ells. J. Exp. Med.172:1471-82112. Stoekinger,B., Pessara,U., Lin, R. H.,Habicht, J., Grez, M., Koch,N. 1989.A role of In-associated nvariant chainsin antigenprocessing nd presentation.Cell 56:683-89113. Steinman, R. M., Cohn, Z. A. 1972.The uptake, distribution and fate ofsoluble horseradish peroxidase inmouse eritoneal macrophagesn vitro.J. Cell Biol. 55:186-204114.Barker, C. F., Billingham,R. E. 1968.Therole of afferent lymphatics n therejection of skin homografts. . Exp.

DENDRITIC CELLS 295Med.128:197-221115.Frey, J. R., Wenk,P. 1957. Exper-imental studies on the pathogenesisofcontact eczeman the guineapig. Int.Arch. Allergy Appl. lmmunol.11: 81-100

116. Inaba, K., Steinman, R. M. 1986.Accessory cell-T lymphocyte nter-actions: antigen dependentand inde-pendentclustering. J. Exp. Med.163:247-61117. Steinman, R. M., Cohn, Z. A. 1973.Identification of a novel cell type inperipheral lymphoid rgansof mice. I.Morphology,uantitation, tissue dis-tribution. J. Exp. Med.137:1142-62118. Inaba, K., Romani,N., Steinman, R.M. 1989. Anantigen-independentcon-tact mechanisms an early step in T-cell proliferative esponseso dendriticcell. J. Exp. Med.170:527-42119.Landry, D., Doyon,L., Poudrier, J.,Lafontaine, M, Pelletier, M, Mont-plaisir, S. 1990. Accessory unctionof humanhymicdendritic cells in acon A-inducedproliferation of auto-logous thymocyte ubsets. J. Immunol.144:836-44120. Inaba, K., Steinman,R. M.1987. Mono-clonal antibodies to LFA-1and toCD4nhibit the mixed eukocytereac-tion after the antigen-dependentlus-tering of dendritic cells and T lym-phocytes. J. Exp. Med.165:1403-17121. Austyn, . M., Morris,P. J. 1988.T cellactivation by dendritic cells: CD18-dependentlustering s not sufficient formitogenesis.Immunology3:537-43122. Koide, S. L., Steinman, R. M. 1987.Induction of murine interleukin-l:stimuli and responsive primarycells.Proe. Nail. Aead. Sei. USA 4: 3802-16123.Bhardwaj,N., Lau, L., Rivelis, M.,Steinman, R. M. 1988. Interleukin-1production by mononuclear ells fromrheumatoid ynovial effusions. Cell.Immunol.114; 405-23124.McKenzie,. L., Prickett, T. C. R.,Hart, D. N. J. 1989. Humanendriticceils stimulateallogeneicT cells in theabsence of IL-1. Immunology7: 290-97125. Vakkila, J., Sihvola, M., Hurme,M.1990. Humaneripheral blood-deriveddendritic cells do not produce nter-lcukin-1 alpha, interleukin-1 beta, orinterleukin-6. Seand. J. Immunol. 1:345-52126.Sauder, D. N., Dinarello, C. A.,Morhenn,V. B. 1984. Langerhans ellproduction f interleukin-1. J. Invest.DermatoL82:605-7


Annu.Re

v.


rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


26/28

296 STEINMAN127. lnaba, K., Witmer-Pack,M.D., Inaba,M., Muramatsu,S., Steinman, R. M.1988. The function of Ia dendriticcells, andIa- dendriticcell precursors,in thymocytemitogenesis o lectin andlectin plus IL-1. J. Exp.Med.167:149-

62128.Naito, K., Inaba, K., Hirayama,Y.,Inaba-Miyama,M., Sudo, T., Mura-matsu, S. 1989. Macrophage actorswhich enhance the mixed leukocytereaction nitiated by dendriticcells: J.Immunol.142:1834-39129. Steiner, G., Tschachler, E., Tani, M.,Malek,T. R., Shevach,E. M., Holter,W., Knapp,W., Wolff, K., Stingl, G.1986. Interleukin 2 receptors on cul-tured murine epidermal Langerhanscells. J. Immunol. 37:155-59130. Makgoba, M. W., Sanders, M. E.,Shaw, S. 1989. The CD2-LFA-3 ndLFA-I-ICAMathways; relevance toT-cell recognition. Immunol. oday10:417-22131. Langhoff, E., Steinman, R. M. 1989.

Clonal expansion of human T lym-phocytesnitiated bydendriticcells. J.Exp. Med. 169:315-20132. Pancholi, P., Steinman,R. M., Bhard-waj, N. 1990.Dendritic ell-T cell clus-ters are an enriched ource or selectingantigen specific CD4+ T cell clones.Submitted133.Matzinger,P., Guerder, S. 1989. DoesT-cell tolerance require a dedicatedantigen-presenting cell? Nature338:74-76134. Inaba, M., Inaba, K., Hosono, M.,Kumamoto, T., Ishida, T., Mur-amatsu, S., Masuda,T., Ikehara, S.1990. Distinct mechanismsof neo-natal tolerance induced by dendriticcells and thymicB cells. Submitted135.Fairchild, P. J., Austyn,J. M. 1990,Thymic endritic cells: Phenotype ndfunction. Int. Rev. Immunol. :187-96136. Schild, H., Rotzschke,O., Kalbacher,H., Rammensee, .-G. 1990. Limit ofT cell tolerance o self proteinsby pep-tide presentation. Science247:1587-89


Annu.

Rev.

Immunol.1991.9:271-296.

Do

wnloadedfroma

rjournals.annua

lreviews.org


08/15/07.

Forpersonaluseonly.


27/28

Annu.

Rev.Immunol.1991.9:271-296.

Down

loadedfroma


byRockefellerUniversityon08/

15/07.

Forpersonaluseonly.


28/28

Annu.

Rev.Immunol.1991.9:271-296.

Down

loadedfroma


byRockefellerUniversityon08/

15/07.

Forpersonaluseonly.

1991 Ann Rev Immunol

Documents

Transcript of 1991 Ann Rev Immunol