contemporary models for peripheral tolerance and the classical ‘historical postulate’

doi: 10.1006/smim.2000.0235, available online at http://www.idealibrary.com onseminars in IMMUNOLOGY, Vol. 12, 2000: pp. 221229

Contemporary models for peripheral tolerance and theclassical historical postulate

Peter Bretscher

The formulators of Clonal Selection Theory proposed thatwhat distinguishes self from foreign antigens is their earlyappearance in development, and their continuous presencethereafter. This early presence of a self antigen in an animalslife history was envisaged to ensure that lymphocytes specificfor the self antigen were silenced rather than activated. I callthis idea the historical postulate. Contemporary models forthe activation/inactivation of helper T cells implicitly violatethis postulate. I argue against such a violation and for amodel of T helper cell activation/inactivation that reconcilescontemporary observations with the postulate.

Key words: peripheral tolerance / historical postulate / Thactivation / inactivation / two step, two signal model

c 2000 Academic Press

Introduction

I shall try to set the ground for discussing centralissues by first outlining a framework that most canaccept and that, in my perception, most probablyallows a legitimate discussion of central questions.I shall put caveats in parentheses and thus avoidelaborate justification of relatively minor points whichmust be touched upon to achieve a frameworksuitable for discussion.

I believe most contributors to this volume wouldagree to the likelihoods that:

(i) (Most) T cells are generated in the thymus and,if they encounter there a sufficient concentration ofa self antigen for which they are specific, they are

From the Department of Microbiology and Immunology, University ofSaskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.

c2000 Academic Press10445323/00/030221+ 09/$35.00/0

deleted or rendered anergic.1 Lymphocytes specificfor extra-thymic or peripheral self antigens are ex-ported from the thymus.2, 3 There are mechanisms bywhich antigen can either inactivate or activate theseperipheral mature T cells.4

(ii) The activation of (most) B cells, and (at leastsome) CD8 T cells, requires the presence of antigenand activated CD4 T cells (reviewed in Reference 5).

(iii) The interaction of antigen with (most) restingB cells and (at least some) resting CD8 T cells, in theabsence of activated CD4+ T cells, results in theirinactivation. In this sense, CD4+ T lymphocytesare the guardians over the activation/inactivationof other lymphocytes: if there are no CD4 T cellsspecific for self antigens, these antigens cannotactivate (most) specific B cells or (at least some)CD8 T cells, but will inactivate them, so long as theantigens are present at a sufficient concentration.

The original two signal model

These conclusions are consistent with the spirit ofthe original two signal model6 and are generally be-lieved to have considerable but not absolute validity[e.g. see (caveats) above]. The original two signalmodel, formulated long before MHC-restrictedrecognition of antigen by T cells was envisaged,appeared to provide a mechanism by which theimmune system could generate an immune responseto foreign antigens under most circumstances andremain unresponsive to self antigens, see below. Inthe modern context, it is recognized that centraltolerance for T cells is established in the thymus andthat peripheral mechanisms of T cell inactivationexist. The original two signal model, see Figure 1,can account for peripheral tolerance in the followingmanner. The activation of all resting antigen-specificlymphocytes, i.e. B cells, CD4+ and CD8+ T cells,requires the presence of antigen-specific T helper

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effectorT helper

cell

restinglymphocyte

precursor cell

receptor

antigen

receptor

2

11

Figure 1. The original two signal model.

(Th) cells; if these lymphocytes interact with antigenin the absence of such Th cells, they will be (canbe) inactivated on interacting with the antigen. Thusthe first single lymphocyte generated specific fora particular self antigen will be inactivated by theself antigen (if present at sufficient concentrations),and further lymphocytes specific for the antigenwill be inactivated as they are generated one (or afew) at a time. In contrast, lymphocytes specific fora foreign antigen F, but not for any self antigen, canaccumulate in the absence of F. Once F impingesupon the immune system, F can mediate the inter-action between the accumulated lymphocytes that isrequired to obtain an anti-F response.

Most agree that the original two signal modelapplies to the activation/inactivation of (most) B cellsand of (at least some) CD8+ T cells. The mechanismscontrolling the activation/inactivation of CD4+ Tcells are therefore the crucial issue. This is also theissue around which there appears to be the highestdensity of conflicting views. I address this issue here.

Different paradigms and the elaboration ofthird signal models

The original two signal model represented a partic-ular proposal for satisfying a more general argumentthat has driven much immunological thought in thepast. This argument was directed at understandingthe nature of self tolerance, but has been ignored orfound wanting by many contemporary discussants. I

shall therefore outline this argument.Many of the pioneers of Clonal Selection Theory,

including Burnet,7 Jerne8 and Lederberg,9 were cen-trally concerned about how self tolerance might beachieved. These pioneers supposed that the attributeof a self antigen that distinguishes it from foreign anti-gens was its appearance at a time before competence hadbeen achieved by the immune system to respond to the anti-gen in question and by its presence continuously there-after. Thus, whether a newly generated lymphocytespecific for an antigen was activated or inactivated inthe presence of the antigen depended not only onthe circumstances at this time, but also had in gen-eral to depend upon whether this antigen had beenaround previously. Thus the decision whether or notto make an immune response against an antigen wasenvisaged to depend on the past history of the immunesystem with respect to exposure to this antigen. I re-fer to this idea as the historical postulate. One way ofsatisfying this postulate is by the mechanism incorpo-rated in the original two signal model. This statedthat a single (or very few) lymphocytes specific for anantigen would be inactivated upon interacting withthis antigen, as the competitive process of activationrequires collaboration between lymphocytes specificfor the antigen, and this process would be impossiblefor single lymphocytes and not favoured when suchlymphocytes are scarce.

Many classical experiments support the historicalpostulate.1012 However, the significance of theseobservations must be reconsidered in light of theexistence of central and peripheral tolerance. It hasbeen established that the historical postulate is validfor central tolerance at the T cell level.1 Does a similarlearning mechanism of what is self and what is foreignalso apply for mature CD4 T cells? In other words,is there a mechanism of peripheral tolerance at theCD4 T cell level that satisfies the historical postulate?This is the central issue for me.

Janeway has been a pioneer in linking non-immuneor innate defence mechanisms to how the immunesystem functions.13, 14 He postulates that there is amandatory requirement for the activation of innatedefence mechanisms for the initiation of immuneresponses. His viewpoint also implicitly denies thevalidity of the historical postulate as it bears onperipheral tolerance at the level of CD4+ T cells,see below. Janeways view has been elaborated uponby Matzinger15, 16 and Zinkernagel.17, 18 I now tryto outline the nature of Janeways argument, andsubsequently the reasons I find it unsatisfactory.

Janeway postulates that the interaction of a precur-

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Peripheral tolerance and the historical postulate

pTh cell

TcR

class II MHCmolecule

costimulation

costimulatormolecule

1

2

1

APC

MHCclass IIbearing

cellcounter

receptor toostimulatormolecule

Figure 2. The contemporary model for the activation ofpTh cells. According to some, signal 2 is constitutive,according to others it is inducible, recquiring a third signalgenerated by infectious nonself or danger. According toothers the generation of signal 2 requires activation of theAPC by activated T cells.

sor Th (pTh) cell via its TcR with the antigen gener-ates signal 1. A second signal, signal 2, or a costimula-tory signal, can be generated in a number of ways, forexample through the interaction of B7 on APC andCD28 on CD4 T cells, see Figure 2. The generationof signal 1 alone inactivates the pTh cell. The genera-tion of both signals 1 and 2 is required for activationof the pTh cell, see Figure 2. Thus the ability to gener-ate the costimulatory signal is critical to whether theresting CD4 T cell is activated or inactivated. Janewaysuggests that the formation of a competent costimula-tory signal requires the generation of a third signal weshall call signal 3. Signal 3 might act in diverse ways.It could act on an APC to cause the APC to express acostimulatory molecule such as B7. It could act on theCD4 T cell itself, generating signal 2 more directly.However, Janeway envisages that signal 3 is always re-quired to initiate an immune response.13

Janeway, in developing his viewpoint, points outthat most purified antigens derived from non-microbial sources, in contrast to infectious agents,are not immunogenic unless administered with anadjuvant that contains microbial components. Thisgeneralization contains some truth. Most ideas onwhat is involved in initiating immune responses

do not take account of this need for adjuvants,and Janeway has consequently referred to this asthe immunologists dirty little secret. He suggeststhat innate defence mechanisms must have evolvedmultiple means of detecting pathogens, surely aplausible proposition. He also postulates, however,that the immune system relies upon these meansto decide whether or not to respond to an antigen.In other words, he proposes that the means fordetecting pathogens by innate defence mechanismshas been commandeered by the immune system todecide whether to initiate an immune response: suchan interaction between the microbial component(s)and innate defence mechanisms generates signal 3,required for signal 2 generation, required in turnfor the initiatiation of an immune response to theantigen. In this manner, Janeway postulates that theimmune system discriminates between noninfectiousself and infectious nonself rather than between selfand foreign antigens.13 Janeways arguments areinteresting and have been very influential. Matzingerhas extended Janeways proposals to suggest stresssignals are the overriding generator of signal 3.13, 14

Matzingers third signal is called the dangersignal.15, 16

Why third signal models are unappealing

(i) The need for a mechanism of peripheral tolerance

Matzinger has argued that a mechanism of peripheraltolerance does not exist. Part of the grounds for herview is that she cannot see an unambiguous way ofdifferentiating peripheral self from foreign antigens.She does not consider the historical postulate andimplies there is no need for a mechanism of periph-eral tolerance.15 However, autoimmune diabetes,Hashimotos thyroiditis, and pernicious anemia allappear to reflect a failure in peripheral rather thancentral tolerance, and can be devastating diseases.Observations in rats and mice show that lymphocytesspecific for antigens expressed in an organ-specificmanner are exported from the thymus.2, 3 Thisstrongly suggests that there is a mechanism of pe-ripheral tolerance for organ-specific antigens thatcan be subverted or can malfunction to give rise tothe striking pathology associated with organ-specificautoimmunity. The existence of these pathologiesstrikes me as making a compelling case for the valueof a mechanism of peripheral tolerance. In addition,an experimental ability to induce and/or prevent the

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generation of organ-specific autoimmmunity shouldgive clear insights into what is critical to controllingwhether peripheral CD4 T cells are activated orinactivated, and hence into the basis of peripheraltolerance. This is a point to which I shall return atthe very end of this contribution.

(ii) Our knowledge of the art of immunization does notprovide a priori grounds for third signal models

Many non-microbial antigens are highly immuno-genic even when administered without adjuvant,contrary to Janeways assertion, as discussed below.I believe the tendency that Janeway has drawn at-tention to, namely that many studies involve the useof weak antigens against which the generation ofsubstantial immunity is best achieved with the aid ofadjuvants, has a natural explanation. Firstly, studieswith highly immunogenic antigens do not allow oneto easily vary the conditions of immunization andthereby increase the immune response, thus provid-ing clues as to what is needed to obtain a response,whereas studies with weak antigens do. Secondly, itis relatively difficult if not impossible to obtain in animmunocompetent animal a specific unresponsive stateby administering highly immunogenic antigens. Im-munologists have often wished to do just this becausethey are interested in what controls whether a stateof unresponsiveness or of immunity follows exposureto antigen. They therefore employ what they havediscovered to be weak antigens, as they can givethese antigens in slightly different ways and generatealternative states of specific unresponsiveness orimmunity. Aggregation of the antigen, or employingan adjuvant, are some favourite manoeuvres thatpromote immunity. Interestingly, weak antigens areoften serum proteins taken from related vertebrates,such as bovine serum albumin or foreign insulins inmice, antigens yielding few CD4 T cell-recognizedforeign peptides. The weakness of these antigensis anticipated on the original two signal model,as such antigens, in contrast to similarly sized bac-terial antigens, will give rise to relatively few Thcell-recognized foreign peptides and there will con-sequently be relatively few Th cells specific for theseantigens. This scarcity will make the specific pThcell/Th cell interaction, envisaged to be required toinitiate an immune response, relatively difficult toachieve.

Many non-microbial antigens are immunogenicwhen administered without adjuvant. Sterile xeno-geneic red cells are universally immunogenic in mice

when administered without adjuvant. Exposure ofrhesus factor negative (Rh) mothers to Rh+ fetalred cells often leads to the production of anti-Rhantibody. This means, in the context of Janewaysframework, that Rh red blood cells must be able togenerate signal 3 in people. Given the abundanceof such cells in Rh+ individuals, all such individualsshould have organ-specific autoimmunity due to theconstitutive generation of signal 3. This argumentapplies to all alloantigens within a species that areimmunogenic, such as the H-Y male antigen. The factthat virtually all sterile xenogeneic red blood cellsare immunogenic in mice implies, within Matzingersformulation, that all such injections generate dangersignals, with the consequent possibility that organ-specific autoimmunity will be induced. This stretchesmy credulity.

(iii) Third signal models violate the historical postulate

Third signal models state that whether a newlygenerated CD4 T cell is activated by its specificantigen depends only upon the circumstances at thistime (i.e. whether these circumstances lead to thegeneration of signal 3) and not on the past historyof the immune system with respect to this or related(crossreacting) antigens. These models thus implicitlydeny the validity of the historical postulate.

I do not like this, as the historical postulate is theonly plausible means I have personally been able toenvisage for operationally defining the difference be-tween peripheral self and foreign antigens. I believethe immune system achieves this for the reasons out-lined in the next sections.

Hanahan and colleagues attempted to addressthe issue of the historical postulate some years ago.They constructed mice transgenic for the SV40T antigen expressed under the control of the ratinsulin promoter, with the reasonable hope that theantigen would be expressed predominantly in/on islet cells. Different transgenic mouse lines weregenerated and were found to express the T antigenat different times of development. Lines that expressthe T antigen early are tolerant of it and strains thatexpress the T antigen later produce antibodies to itand their pancreas is infiltrated by lymphocytes.19

These observations appeared highly supportive ofthe view that the historical postulate applies toperipheral tolerance, with one caveat. The T antigenshould not be expressed at significant levels inthe thymus as the observations, in this case, mightreflect central rather than peripheral tolerance.

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Unfortunately, this question is not clearly settled.20

Nevertheless, Hanahans experiments illustrate thekind of experiment that can resolve the issue of therelevance of the historical postulate for peripheraltolerance. Given the currently available techniquesto control the site and timing of expression oftransgene-encoded antigens, it seems likely that suchexperiments will be carried out in the near future.

The historical postulate does not imply that thereis a unique time around birth when the immunesystem is susceptible to establishment of tolerance,as Matzinger states.21 It has been known for decadesthat animals may be competent to mount immuneresponses before birth to some antigens and, in atleast some of these cases, unresponsiveness can begenerated by administering the antigen before suchcompetence has been achieved (e.g. References 22,23).

(iv) Specificity and regulation of the immune response

The immune system employs many innate mech-anisms of defence that are older phylogeneticallythan itself to achieve its own ends. Antibody is thesticky adaptor that brings into proximity the antigenand various phylogenetically older innate defenceweapons, such as complement, phagocytic cells, andmast cells able to release mediators of acute inflam-mation. Antibody, complexed to the invader, canactivate these weapons. Similarly, T cells bring IFN ,for example, to the surface of virally infected cells.What advantages to defence does the immune systemprovide vertebrates over these phylogenetically olderinnate defence mechanisms? It is transparentlyobvious to me, and I hope to others, that a majoradvantage is specificity, allowing the discriminatingdelivery of attacking mechanisms as a result of highlyeffective self-nonself discrimination. A major force inlimiting the further evolution in the aggressiveness ofthe weapons of innate defence is the lack of exquisiteself-nonself discrimination. The more damagingthese innate mechanisms are to foreign invaders,the more damaging will they be to self, due to thesloppiness of the process directing them uniquely toforeign objects.

In view of such considerations, I consider mech-anisms by which specificity can be achieved to becrucial. Consider what we have learnt concerning theinteraction between resting B cells and activated Thcells that leads to B cell activation. An anti-hapten Bcell can normally only be helped by an anti-carrierspecific T helper cell in the presence of the hapten-

carrier conjugate h-C, but not when both hapten andcarrier are present but in unlinked form, such as inthe presence of h-Q and C, where Q and C do notcrossreact. I refer to these requirements by sayingthat a functional B cell/Th cell interaction requiresthe (operational) recognition of linked epitopes. Inother words, a Th cells mechanism of action is shortrange in nature, thus ensuring specifity of action.

It is generally acknowledged that (most) B cells and(at least some) CD8+ T cells require Th cells for theiractivation. In this sense, Th cells are the guardiansover the activation of other lymphocytes. However,they can only be good guardians to the extent thattheir own activation is well regulated to ensure thatonly anti-foreign pTh cells are activated.Third signalmodels imply that whenever any immune responseoccurs, a third signal must be generated, and thatthere is a real potential under such circumstancesfor the induction of organ-specific autoimmunity viathe activation of pTh cells specific for organ-specificantigens. The postulated third signal processesundermine specificity. Indeed, even within thecontext of the original two signal model, it onlymakes physiological sense to me if the pTh/Th cellcollaboration postulated to be required to activatethe pTh cell involves the obligatory recognition oflinked epitopes. Only in this case can we ensure thata response to a foreign antigen F will not activate pThcells specific for an organ-specific antigen, O, whereF and O do not crossreact. We successfully tested theproposition that the activation of pTh cells yieldingTh cells mediating delayed-type hypersensitivityrequires pTh cell/Th cell collaboration, occuringby the operational recognition of linked epitopes,a number of years ago.24 The new model I haveproposed explains how such linked recognition canbe achieved.5

A reconciliation between the historical postulateand contemporary observations

I have recently published an attempt to achievethe above aim.5 I decided, when invited by theEditors of this volume to contribute to it, that itwould be more profitable for discussion if I laidbare some of my uneasiness about the argumentsinspiring contemporary models of others, which Ihave not done elsewhere, rather than stating thepositive grounds for the model I favour, which I haverecently done.5 Indeed, I find that a formal andpositive exposition of a given view often does not do

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constitutivecostimulator

moleculeInducible


class IIMHC molecule

costimulationcostimulation

STEP 1 STEP 2

counterreceptor to


counterreceptor to


pTh cell

TcR TcR

APC APC



activationsignal

MHCclass IIbearing

cell

MHCclass IIbearing

cell

eThcell

1

1

1

1

22

step oneprimed

pTH cell

Figure 3. A two step, two signal model. For explanation, please see text.

full justice to the tortuous mental paths undergonein arriving at the view. It takes little account ofthe processes of eliminating the impossible/veryimprobable. Such processes are critical to findinga paradigm attractive that initially appears to becomplex or unlikely. We are not normally given anopportunity to give an account of what really drivesthe development of a viewpoint. What follows is anaddition to the manuscript I originally sent RodLangman and written in two days at his request. Ihope that the above long introduction to a briefdescription of my own positive view is helpful, becauseI regard it as reflecting essential mental processesneeded to assess what follows.

Contemporary observations are difficult toreconcile with the original two signal model asdepicted in Figure 1. There are four sets of obser-vations/considerations that could be considered torender this model implausible. The new model is anattempt to conserve what I believe is conceptuallymost valuable from the original two signal model,and to construct an even more physiologically plausi-ble framework that is consistent with contemporaryobservations. I shall briefly outline the new modeland then describe how it attempts to overcome thesefour sets of observations/considerations.

The two step, two signal model for the activationof CD4+ T cells is depicted in Figure 3. A restingCD4+ T cell, specific for the nominal antigen Q, inorder to become fully activated, first interacts with

Q presented by an APC that constitutively expressesthe necessary costimulatory molecules. Such APCare likely to be macrophages or mature dendriticcells. This is envisaged to cause the interactingCD4+ T cell to divide on receiving two signals. Theresulting proliferating CD4+ T cells will die unlessthey complete a second step. This involves theirinteraction with a B cell, specific for Q, that hasingested Q via its Ig receptors, and bears peptidesq1, q2, . . . . qn, derived from Q and associated withthe B cells surface MHC class II molecules. The Bcell, in order to function as an APC in activating theCD4+ T cells through step 2, must itself have beenactivated to express certain costimulatory moleculesby an activated CD4 T cell specific for the nominalantigen Q. Activation in this second step requirestwo signals again, but this second second signal,signal 2, must be different from the first signal 2,otherwise the second step could not be differentiatedfrom the first step, and hence step 2 could not bemandatory for activation.

The problems this model attempts to solve are:

(a) The problem of constitutive costimulation

Costimulatory molecules are sometimes constitutivelyexpressed and are sometimes inducible.25 There isno role for constitutive costimulation in the originaltwo signal model, but the pertient observations areaccounted for by the first step of the new model.

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(b) The problem of recognition of linked epitopes by T cells

We now know that most T cells see antigenic peptidesbound by MHC molecules, a finding quite unantici-pated when the original two signal model was formu-lated. How can the operational recognition of linkedepitopes in the CD4+ T cell/CD4+ T cell interaction,envisaged to be required for CD4+ T cell activation,occur? In order to complete step 2, Q is endocytosedby the presenting B cell via its Ig receptors, and Q-derived peptides bound to MHC class II moleculesare expressed on the B cells surface. A Q-specific ac-tivated CD4+ T cell can thus activate the B cell to ex-press the costimulatory molecules necessary for the Bcell to further stimulate the step 1 primed Q-specificCD4T cells through step 2. As both the activated andstep 1 primed T cells are specific for Q, this processinvolves the cooperation of the two CD4+ T cells viathe operational recognition of linked epitopes.

(c) The scarcity problem

Unprimed lymphocytes specific for a given antigenare scarce. The question whether such scarce cellscould find one another to initiate a primary responsewas recognized as a point of serious considera-tion when the original two signal model was firstproposed.6, 26 The two step, two signal model mayprovide a partial solution to this concern, as the firststep does not involve an interaction between two rarecells, but results in the proliferation of one of them,making the occurrence of the initial cell interactionbetween rare cells types, and postulated to occur instep 2, more easy to envisage, and hopefully to occur.

(d) The priming problem

There is a requirement for activated CD4+ T cells forthe activation of resting CD4+ T cells. Where doesthe first activated CD4+ T cell come from? Thereare many analogous questions in biological systems,such as where did the first ribosome come from, giventhat ribosomes are needed to synthesize ribosomalproteins. This consideration was also evident early onand is referred to as the priming problem.26

The antibody response is susceptible to X-ray ra-diation,27 due to the radiation-sensitivity of dividingcells, including B cells. The ability of pTh cells to beinduced by antigen to yield eTh cells is similarly sen-sitive to irradiation, but the activity of eTh cells, oncegenerated, is radiation resistant.24 This makes sensein that the generation but not the expression of eTh

activity requires T cell multiplication. There is a spec-trum of antibody-producing cells in a mature mousenot deliberately immunized. These cells maintain thelevel of serum immunoglobulin. Such on-going an-tibody responses are likely Th-dependent, implyingthe existence of a spectrum of eTh cells in a maturemouse not immunized by an immunologist. Observa-tions support this reasoning. Radiation-resistant eThcells can be detected in the spleen of unimmunizedmature mice.27 How could such a spectrum of eThcells arise?

The existence of a few effector Th cells neonatallymay, in the continuous presence of an appropriatevariety of foreign antigens and spectrum of pTh cells,yield a wider spectrum of eTh cells, in accord with theprecepts of the two step, two signal model. Thus thepriming problem may be reduced to understandingthe origin of a few effector Th cells neonatally. Thedifference between the neonatal pTh cell populationspecific for a foreign and for a peripheral self antigenis in the number of cells available. The greaternumber of cells specific for a foreign than a selfantigen could allow the foreign but not the selfantigen to generate some eTh cells. This could occurif, for example, the foreign antigen was present andpTh cells were endowed with some basal effector Thactivity around birth.26

Finally, I wish to make three points about the newmodel. It explains peripheral tolerance at the CD4+T cell level in a way analogous to that provided bythe original two signal model. This is by virtue ofthe inactivation of CD4+ T cells on interacting withantigen in the absence of activated CD4+ T helpercells, i.e. if the step 1 primed T cells do not completestep 2.

Secondly, the postulated requirement for B cells asAPC in step 2 appears to be in conflict with a numberof reports showing that immune responses can bemounted by B cell knock-out mice (discussed in 5).My response to this is two fold. I recall a commentmade by Francis Crick during a seminar held in theearly 70s on the philosophy of scientific enquiry. Itwent something like this: You can bet that a theorythat explains all the facts is wrong, as some of thefacts are always wrong, and a theory that explainsuntruths must, logically, be wrong. In addition, thereis some evidence suggesting that the B cell knock-outmice employed in many of these studies are leaky andthat other B cell knock-out mice are less so and givedifferent results.28 In view of this, I think it reasonablenot to discard the new model out of hand on the basisof this evidence against it.

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Lastly, a whole series of observations concerning theinduction of autoimmunity fit in with the new model.These include epitope-spreading at the CD4 T celllevel, a phenomenon predicted by the requirementfor CD4+ T cellCD4+ T cell collaboration in the ac-tivation of resting CD4+ T cells (see 5). We have seenhow an understanding of the B cell/Th cell interac-tion has allowed us to understand how antigens thatcrossreact with self antigens can induce autoantibody.This reality is not denied. However, both the originaltwo signal and the two step, two signal model pre-dict that antigens that crossreact with peripheral anti-gens have the potential to cause organ-specific CD4+T cell autoimmunity. We understand how infectionwith group A streptoccoci can induce autoantibodiesto heart tissue due to a crossreaction between hearttissue and this pathogen. We do not on this basis denythat anti-self B cells can be inactivated on interactingwith antigen in the absence specific Th cells, thoughthe incomplete lack of elimination of these B cellscould be called immunological ignorance. However,I prefer to recognize it as a result of quantitative or dy-namic considerations. These suggest that either thereare newly generated B cells, and/or B cells specific forself antigens present at too low a level to achieve effi-cient B cell elimination, that can be activated by anti-gens that crossreact with the self antigen. Similarly,the observations showing that a virus can induce dia-betes in mice transgenic for a viral antigen expressedon islet cells is understandable,29 as is the inductionof encephalitis by Theilers virus.30 Indeed, the mostobvious way by which antigens crossreacting with selfantigens can arise is by infection of self cells by in-tracelllular parasites. On the other side of the coin,it seems it should be possible to prevent, and possi-bly treat, CD4+ T cell autoimmunity by administeringmonovalent T cell antigens. The evidence, reviewedin 5, is certainly not against this possibility.

Acknowledgements

This work was supported by grant MT-14121 fromthe Medical Research Council of Canada. I thankCarl Power and Tara Strutt for critical reading of themanuscript.

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IntroductionThe `original' two signal modelFig. 1

Different paradigms and the elaboration of third signal modelsFig. 2

Why third signal models are unappealingFig. 3

A reconciliation between the historical postulate and contemporary observationsReferences

contemporary models for peripheral tolerance and the classical ‘historical postulate’

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