The two-signal model of lymphocyte activation twenty-one years later

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The two-signal model of lymphocyte activation twenty-one years later

Peter Bretscher Here, Peter Bretscher discusses the extent to which the predictions of the two- signal model have been fulfilled, and whether the current paradigms provide a

satisfactory explanation of self-nonself discrimination.

The essence of the original two-signal modeP was that the induction (activation) of clonal precursor cells requires antigen-mediated interaction with other, antigen- specific, clonal cells, whereas an interaction of antigen alone with the clonal precursor cell leads to its paralysis (that is to its deletion or to it being rendered anergic, in more modern terminology). Such rules incorporate a mechanism of self-nonself discrimination. Precursor cells specific for a self antigen, S, are expected to be inactivated by S when they first arise, as there are no other specific cells with which they can cooperate to be induced. Further anti-S precursor cells will also be inactivated as they are generated one, or a few, at a time. Precursor cells specific for a foreign antigen, F, will accumulate in the absence of F, and can collaborate to mount an immune response once F impinges upon the immune system 1. The paralytic signal is referred to as signal 1 and the signal resulting from the specific-cell- specific-cell interaction and delivered to the precursor cell is referred to as signal 2 (see Fig. l(a)). We suggested that signal 2 might involve a membrane-membrane interaction and/or the delivery of short-range soluble mess- enger molecules, or interleukins in modern terminology.

In the accompanying article, Marc Jenkins concisely reviews many recent observations that are best under- stood in terms of the two-signal model 1, and further elaborates upon this model. Here, I discuss the extent to which the three predictions of the model have stood the test of time, and describe a central paradox in our understanding of self-nonself discrimination.

Evidence supporting the three predictions First, the prediction that induction of all subsets of

lymphocytes requires inducer T cells has been verified for precursor B cells that can be induced to produce IgM, lgG, IgE and IgA antibody 2~, and for T cells, the progeny of which exhibit specific cytotoxicity or delayed-type hypersensitivity s-7. It has not been so clearly established for the precursors of inducer T (pTl) cells (see below).

Second is the prediction that inducer T cells perform their function by generating second signals. The name 'helper T cell' reflects the view, widely held for several years following our two-signal proposal, that such cells are not necessary for the induction of precursor cells. 'Helper T cells' were thought by many merely to concen- trate or present antigen in a manner that increased the efficiency of, but was not essential for, the induction of lymphocytes; this view is inconsistent with many observations, including a requirement for interleukins in the

activation of lymphocytes (M. Jenkins, this issue). 1 refer to these cells as inducer T (T,) cells as opposed to T,, cells, to reflect their mandatory role in the induction of immune responses.

Third is the prediction that the interaction of antigen with the receptors of a precursor cell, in the absence of inducer T cells, renders it anergic to subsequent stimu- lation. Clear evidence in favour of this proposition was first obtained by Klinman and colleagues 8 using single B cells. Jenkins reviews much recent evidence, including the elegant experiments by Goodnow, Basten and colleagues 9,1°, and by Guerder and Matzinger H, supporting the view that this prediction is true for mature, inducible B cells and for inducible, extrathymic precursor cytotoxic T lymphocyes (pCTL).

The current dilemma: regulation of peripheral inducer T cells

Recent studies by Jenkins, Schwartz and colleagues show that resting cells, derived from inducer T-cell clones, require two signals to be activated (see Fig. l(b)). Marc Jenkins (this issue) describes the evidence supporting this mechanism, that the generation of signal 1 alone is paralytic, and that the induction and paralysis of extrathymic precursor inducer T cells occur by similar mechanisms.

The requirements for inducing and paralysing B cells and extrathymic pCTL appear to be correctly described by the two-signal model. This means we have an explanation for mature B-cell and extrathymic pCTL tolerance to self antigens, as long as there are no effective inducer T cells specific for self antigens. Can the two-signal mechanism of inducer T-cell activation outlined in Fig. l(b) provide a basis for understanding the paralysis of inducer T cells specific for extratbymic self, but not for foreign antigens? I believe this is a crucial question to which there is no satisfactory answer at present. Three different viewpoints on this question will now be discussed.

The strategic location hypothesis Studies by Lafferty and colleagues ~2 first showed that

there are different kinds of cell bearing major histocom- patibility complex (MHC) class II antigens; those with and those without the capacity to generate the costimulatory signal required for the activation of pT t cells. Cells with costimulatory capacity are said to have the S + phenotype, whereas those without it are said to have the S- phenotype. One proposal for ensuring the establish- ment of tolerance in pT t cells specific for extrathymic

© 1992, Elsevier Science Publishers Ltd, UK.

Immunology Today 74 Vol 13 No. 2 •992

REVIEW

, ~ ~ 1, "~r....... Antigen ~ ~ / ~ J ~ 7 Receptors ~ 'R~

\ .~ ~ k~ v L j ~-~.'~ ~-~ -"x pTi cell ~" C ~ ) Precursor (~)(" ~ ~_____~j/ /4 k._.._ ~

~ cell ~ ~

~ k J ~ ~ ~ ' ~ L~duCerrfaCtor/r - ~ 1/-"~ ( ~ ~-~----""""~ iducer ecepto (~ / v}./ ~ , "-.& Stimulatory

,,r ~ -- peptide

Fig. 1. The original two-signal model (a) and the current paradigm for the signals required to activate pTI cells (h) are shown. The 'inducer factor/ inducer receptor' in (a) is bound to a 'macrophage-like cell' or embedded in the membrane of the 'inducer T cell'. The stimulatory peptide in (b) is bound

to an MHC class II molecule of the antigen-presenting cell.

antigens is that cells with an S- phenotype are strategically located in the vicinity of cells that express such extrathymic self antigens 13. In this case, pT[ cells, specific for the processed extrathymic self antigens, may first meet them as presented by the S- cells, and they may consequently be paralysed.

This hypothesis predicts that there would be no anti- viral response when there is an initial focus of infection near strategically placed S- cells. This kind of nonspecific regulation is not subtle: it does not embody the exquisite specificity displayed by the immune system, and this at a crucial time point from a regulatory point of view. This hypothesis does not seem to be a plausible solution.

Regulation of signal 2 generation: the microbial product hypothesis

Janeway r4 has pointed out that much of our knowl- edge concerning the induction of pT~ cells comes from experiments using simple proteins or peptides given in complete Freund's adjuvant (CFA). He proposes that it is always essential that accessory cells are activated by microbial products, such as those present in CFA, if they are to generate and deliver signal 2 and an immune response is to occur.

Most pT[ cells are eliminated in the thymus (M. Jenkins, this issue). Exquisitely specific mechanisms ensure self-nonself discrimination at the B-cell and extrathymic pCTL level, as long as there are processes to ensure the paralysis of pT[ cells specific for extrathymic self antigens that do not functionally eliminate pT l cells specific for foreign antigens. An insufficiently discrimi- nating process for solving the paralysis/induction decision for extrathymic pTj cells would make a mockery of the exquisitely specific mechanisms controlling the paralysis/induction decision for B cells and peripheral pCTL. The microbial product hypothesis seems implaus- ible on two grounds. First, the activation of accessory cells by such products cannot be regulated so that access-

ory cells deliver signal 2 only to pT I cells specific for foreign antigens and not to those specific for extrathymic self antigens. Second, it is possible to induce and study immune responses to antigens without using CFA or any other adiuvant; these findings appear to contradict this hypothesis.

Our current paradigm (Fig. l(b)), in contrast to Jane- way's hypothesis, does not explain the necessity of using CFA to obtain responses to small protein and peptide antigens. It is therefore particularly interesting to ask what happens when peptides are given alone without CFA. The answer is that the relevant pT I cells are not induced, but are rendered refractory to induction Is. This finding strongly suggests that most accessory cells do not generate and deliver signal 2 constitutively. The use of CFA appears to bypass an essential step that controls the paralysis/induction decision. It seems dangerous to base a model of pT l activation on observations that can be attained only through the use of CFA.

Regulation of signal 2 generation: control hy specific 11 cells

We very nearly have a plausible description of the induction and paralysis of lymphocytes that accounts for self-nonself discrimination and yet it seems impossible to close the circle. What is needed physiologically is clear: to ensure that peripheral anti-self pT I cells are paralysed by signal 1, and anti-foreign pT l cells are usually induced by foreign antigens on the generation of signals 1 and 2. It seems likely that signal 2 is not constitutively generated by accessory cells, as just discussed. It could be suggested, as proposed in our original two-signal hypothesis I, that the generation of this second signal is dependent on the function of T I cells that are specific for the foreign antigen. There is even evidence supporting this hypothesis. Unanue and colleagues 16.17 have shown that pro- duction of interleukin 1 (IL-I), a co-stimulatory-like molecule, by accessory cells occurs subsequent to an

Immunology Today 75 Vol. /3 No. 2 1 ')92

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interaction between the accessory cell, antigen and MHC-compatible and restricted T I cells. I have provided evidence that the primary induction of precursor inducer T cells requires antigen specific T-cell-T-cell collabor- ation, operationally mediated by the linked recognition of antigenic epitopes TM. The use of adjuvants was deliber- ately avoided in these experiments. A requirement for T-cell-T-cell interaction in the activation of pT I cells would be most satisfactory if a model of how such interactions occur, in a manner consistent with our understanding of the specificity of T cells, could be made. How can there be a requirement for the linked recognition of antigenic epitopes if T ceils recognize peptide fragments bound to MHC molecules? The con- clusion that there is a requirement for linked recognition is essential if signal 2 is to be delivered with the requisite accuracy. This is the dilemma as 1 see it. Mitchison 19 has addressed this problem and proposed that only one antigenic particle (a protein molecule or red cell) is taken up by a given accessory cell at any one time, and that two MHC-restricted T cells can cooperate by binding to different peptides derived from this one particle and associated with MHC molecules present on the same accessory cell. This 'three cell cluster' theory is a logically possible and ingenious solution to the conundrum, but not one that seems very plausible. First, the requirement that an accessory cell ingests only one particle at a time seems both too restrictive and unlikely. Second, protein molecules can activate inducer T cells. The three cell cluster theory would require that single peptides, derived from a single protein molecule, bind to class II molecules with a reasonably high degree of probability, a possibility difficult to reconcile with the known binding constants 2°. Further, if peptides could generally bind so well, all MHC class II molecules would be saturated with peptides derived from self antigens.

The only other way of closing the circle that I can imagine is to deny that all TI cells recognize peptides in association with MHC molecules and to propose that most T1 cells induced without CFA recognize relatively intact antigen. However, any proposal exploiting this possibility would also have to explain why so many T I cells have been found that recognize peptides associated with MHC molecules, and also the observations on

which our current paradigm is based. I believe such an alternative may be possible. Such a view is unacceptable to most immunologists, and I recognize the weight of evidence in favour of the current paradigm. I entertain such a possibility only because of the acuity with which I sense the current dilemma.

References 1 Bretscher, P.A. and Cohn, M. (1970) Science 169, 1042-1049 2 Miller, J.F.A.P. and Mitchell, G.F. (1968)J. Exp. Med. 128,801-802 3 Hamaoka, J., Katz, D.H. and Benacerraf, B. (1973)J. Exp. Med. 138,538-556 4 Challacombe, S.J. and Tomasi, T.B. (1980)J. Exp. Med. 152, 1459-1472 5 Keene, J. and Forman, J. (1982) I. Exp. Med. 155, 768-782 6 Pilarski, L.M. (1977).]. Exp. Med. 145,707-725 7 Tucker, M.J. and Bretscher, P.A. (1982)J. Exp. Med. 155, 1037-1048 8 Metcalf, E.S., Schrater, A.F. and Klinman, N.R. (1979) Immunol. Rev. 43,143-183 9 Goodnow, C.C., Adelstein, S. and Basten, A. (1990) Science 248, 1373-1379 10 Goodnow, C.C., Brink, R. and Adams, E. (1991) Nature 352,532-536 11 Guerder, S. and Matzinger, P. (1989) Cold Spring Harbor Symp. Quant. Biol. 54, 799-805 12 Lafferty, K.J., Prowse, S.J., Simeonovic, C.J. et al. (1983) Annu. Rev. Immunol. 1,143-173 13 Markmann, J., Lo, D., Naji, A. et al. (1988) Nature 336, 476-479 14 Janeway, C.A. (1989) Cold Spring Harbor Lab. Syrnp. Quant. Biol. LIV, 1-13 15 Scherer, M.T., Chan, B.M.C., Ria, R. et al. (1989) Cold Spring Harbor Syrup. Quant. Biol. LIV, 497-504 16 Weaver, C.T. and Unanue, E.R. (1986) J. Immunol. 137, 3868-3873 17 Weaver, C.T. and Unanue, E.R. (1990) Immunol. Today 11, 49-55 18 Bretscher, P.A. (1986)J. Immunol. 137, 3726-3733 19 Mitchison, N.A. and O'Malley, C. (1987) Eur. J. Immunol. 17, 1579-1583 20 Unanue, E.R., Harding, C.V., Luescher, I.F. et al. (1989) Cold Spring Harbor Symp. Quant. Biol. LIV, 383-392

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Immunology Today 76 Vol 13 No. 2 1992

The two-signal model of lymphocyte activation twenty-one years later

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