Determinant spreading and the dynamics of the autoimmune T-cell repertoire

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Determinant spreading and the dynamics of the autoimmune T-cell repertoire Paul V. Lehmann, Eli E. Sercarz, Thomas Forsthuber, Colin M. Dayan and Guy Gammon In this article the authors propose a dynamic model of autoimmunity with T-cell recruitment and selection leading to changes in the specificity of the anti-self response during the course of disease. They argue that these change~ are due to alterations in self-antigen presentation that lead to the display of previously cryptic self-determinants. Mechanisms that could underlie this differential self-presentation are proposed. Our understanding of T-cell mediated autoimmunity is derived to a large extent from the study of animal models of disease, for example, experimental allergic encephalomyelitis (EAE). This inflammatory, demyelinating condition can be induced by immunization with central nervous system (CNS) proteins such as myelin basic protein (MBP) or proteolipid protein (PLP), and resembles human multiple sclerosis (MS) ~. Data obtained in the EAE system have led to the notion that autoimmune T-cell responses are restricted to a single self-determinant and utilize a very limited range of Tcell receptor (TCR) genes 2-4. Thus, in disease susceptible H-2 u mice, the early T-cell response focuses on the amino-terminal region of the MBP molecule corresponding to the N-acetylated peptide Acl-9, and the range of T-cell receptors utilized in the recognition of this determinant is confined almost entirely to the V~ gene segments 8.2 and 13. These restrictions in the diversity of the response permit specific immune intervention in EAE both at the T-cell level, by interference witl'~ pathogenic T cells using anti-Vl3 antibodies or by TCR peptide vaccination, and at the MHC level by blocking with anti-class 1I antibodies or by peptide competition (reviewed in Ref. 1). Do similar restrictions occur in human autoimmunity? Is specific immunotherapy a feasible therapeutic approach? The autoimmane T-cell repertoire is dynamic Considerable effort has been directed towards defining the autoreactive T-cell repertoire in many human diseases including MS 5-~°, autoimmune thyroiditis ~'~2, myasthenia gravis 13a4, insulin-dependent diabetes L~and chronic active hepatitis z6. However, interpretation of the data obtained l~as not been conclusive. Some authors provide evid. nce for a restricted T-cell response s-7,n,~s,16while others find significant diversity both in respect to autoantigenic determinants and in the range of TCR genes s-~l'm4. A solution to this apparent contradiction can be proposed based on data obtained in rodent EAE that relate to the MBP-specific repertoire at different time points ~7-2°. These data

show that the expressed aumimmune repertoire is not fixed but evolves during the course of the disease. For example, in {SJL × B10.PL) F~ mice the MBP response is initially restricted to the peptide Ac1-11, but T-cell reactivity to several additional determinants (MBP 35--47, 81-100 and 121-140) can be detected later 2°. Most significantly, the response also spreads to involve these additional determiaants in animals primed with the murine MBP peptide Acl-!~ alone! This clearly shows that naive T cells are activated by peptides derived from endogenous MBP. Most likely, cytokines released by the first wave of Acl-ll specific q cells upregulate self antigen presentation in the CNS, leadmg to ,h,~,.,.actwanon ot a ~ , . u . u wave of T t.~ns--"-recognizing previously cryptic MBP determinants. In addition to intramolecular spreading there is evidence for intermolecular spreading of the murine T-cell response after MBP immunization to involve other CNS proteins such as proteolipid protein (PLP):~''--'. Is 'determinant spreading' an important event in pathogcnesis? Primary immunization with peptides containing second wave MBP determinants can elicit EAE-';, so that it can be assumed that T cells recognizing these determinants will contribute to disease progression when activated at a late stage after priming. Hence, amplification of the response by the recruitment of T cells wit.'.-: additional specificities may be necessary for the development of the full autoimmune syndrome. Interestingly, priming to both MBP and PLP has been detected in patients with MS z4, which is consistent with diversification. Additional CNS proteins may be involved and in chronic MS it is impossible to predict which one might have been the original autoantigen. There is clear evidence that diversification occurs but it is also possible that autoimmune responses may become mo"e restricted at later time points. It has been demonstrated in vitro that repeated stimulation of T-cell lines by antigen leads to selection both for and against certain clonotypes 2s. This may also happen in vi',o.rhrough selective expansion, induction of anergy,

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viewpoint Recurrent Waves of Recruitment

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in established chronic disease if the expressed autoimmune repertoire is too diverse and dynamic. However, such treatment may be useful in the management of early disease. Therapy based on immune suppression or alterations in the profile of cytokine production may be effective even in established autoimmunity due to local bystander suppression caused by the release of inhibitory cytokines such as TGF-I33°.

2nd Wave Priming Intramolecular spreading Intermolecular spreading

I Initial Priming

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Lack of tolerance to cryptic self. Determinant spreading in murine EAE involves the induction of responses to MBP determinants which Time were not immunogenic following peripheral immunizFig. 1. Evolution of the T-cell repertoire expressed during the course ation with the native antigen. This indicates that antigen nresentation in the context of ongoing autoimmunity of autoimmune disease. oiffers significantly from that in the physiological situclonal exhaustion or immune regulatory mechanisms. ation in lymphoid tissues. These differences will be An in vivo selection process could explain the obser- critical because self tolerance is limited to the set of vations of a broad TCR gene repertoire in active MS peptides effectively presented in the thymus or at sites lesions but a restricted repertoire in chronic plaques of peripheral tolerance induction 3~-33. Any other pepwith clear differences in TCR usage among different tide presented (in a target organ) will be perceived as plaques from the same individual 26, as well as the non self. The existence of a peripheral T-cell repertoire predominance of different TCR genes among individuals27. able to respond to cryptic self determinants, which has On the basis of the foregoing observations, the successfully avoided tolera.ce induction, has been disexpressed autoimmune T-cell repertoire appears to cussed elsewhere31. The observations in the EAE model undergo a process of evolution during the progression indicate that under conditions prevailing in autoimof mouse EAE (Fig. 1). We propose that similar events munity, members of this large cadre of autoreactive cells will occur in human organ-specific autoimmunity. In are induced with self peptides that were not previously human diseases, as in EAE, the initial response may be displayed. This occurs because of a variety of mechlimited to a single determinant, in particular if auto- anisms (discussed later), but essentially is based on immunity is initiated by a chance crossreactivity with a upregulation of presentation in general, or on shifts in microbial antigen. Subsequently, determinant spread- peptide hierarchy. It may be imagined that the immune ing, both intramolecular and intermolecular, should system might have sought protection from autoimoccur, leading to a diverse repertoire. Alternatively, munity by evolving a low threshold for tolerance inducautoimmunity may develop as a secondary event via tion during T-cell ontogeny in the thymus. However, intermolecular spreading following a localized T-cell this will not prevent autoimmunity owing to new response, for example to a tissue tropic virus or bac- presentation of a previously cryptic determinant 31,~4. In terium 28a9, and upregulation of self antigen presen- this model, autoimmunity is not the breakdown of self tation. In this case the autoimmune response may be tolerance but its circumvention by the display of deterdiverse at the outset. Chronic antigenic stimulation minants to which the host was never tolerant. may lead to further waves of recruitment with increased diversity, or contraction and selection pro- How cryptic determinants become visible ducing an oligoclonal T-cell population. What are the mechanisms which could produce difThis model explains how the apparently conflicting ferential presentation of autoantigens leading to the findings of restricted versus diverse repertoires in activation of autoreactive T cells and the diversifiautoimmunity reflect the stage of disease studied rather cation of the autoimmune response? Although there is than a fundamental difference in disease pathology. It a large amodnt of data indicating that differential prescharacterizes autoimmune responses as dynamic and entation occurs, the underlying mechanisms have not highly unstable, and this may underlie the variable been studied systematically. The possible mechanisms clinical picture of remissions and relapses often found are summarized in Table 1. There is experimental eviin autoimmunity. As seen in murine EAE, autoimmune dence for differential peptide display by APC of differresponses may spread to determinants that are restric- ent lineages3-~.Such diffe:ences may reflect the reported ted by MHC molecules initially not involved 1~,2°.Thus, variations in the pattern and subcellular localization of even in diseases which are linked to a susceptibility proteases 36, or different levels of invariant chain allele critical for induction of autoimmunity, the expression. Individual cell types express distinct probroadened pathogenic response may involve additional teins and correspondingly generate different sets of MHC molecules. The pa~icipation of non-shared alle- cellular peptides. This will directly affect the profile of les among individual patients with the same suscepti- peptides displayed in association with MHC molbility gene will result in important differences in deter- ecules. Furthermore, the differences in the spectra of minant recognition. This model predicts that selective proteins expressed will affect indirectly, via peptide immunotherapy, pa~:icularly that based on the elimin- competition, binding of any peptide to MHC. ation of specific T cells using anti-TCR antibody or Competition between peptides for the MHC-peptide peptide-induced toler~ ,ace, may be of limited effic:'-,'y binding site has been demonstrated experimentally and Selection/Regulation

b

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viewpoint Table 1, Possible mechanisms leading to dominant display of cryptic self determinants

Cause Antigen-presenting cells of different lineage

Consequence

Different proteases involved in processing Various levels of invariant chain expressed Different proteins expressed Immunoglobulin-mediated protein concentration by antigen specific B cells

Altered pattern of peptides generated Changes in peptide loading Shifts in self peptides produced and competing for MHC binding Higher level of determinants derived from selected protein

Intracdlular versus extracellular origin of antigen

Processing and ,~.'HC-binding in different intracellular compartments A role for transporters of cytosolic peptides

Different profile of peptides produced Differences in peptide loading

Response to cellular stress

Heat shock proteins (hsps) $ House-keeping proteins I" Heat shock protein PBP72/74

Differences in self peptide~ produced

MHC-class II $

Raising the number of previously cryptic MHC-peptide ligands above immunogenic threshold Reduced threshold for T-cell activation

Activation of antigen-presenting cells

Accessory molecules $ (ICAM, LFA-1 etc.) Nominal autoantigen 1" Changes in level of proteins unrelated to nominal autoantigen Increased and differential expression of proteases (some '1",others not) Infection of antigen-presenting cells

Viral proteins and viralinduced cellular proteins 1" Virus-mediated shut-off of host cell translation

Facilitated binding of peptides to MHC

Same as MHC Class II Shift in peptides competing for MHC binding Enhanced processing and generation of altered set of peptides Altered population of peptides displayed

thus the likelihood of a peptide gaining access to MHC OCCUr 11'42"43. This should involve the display of novel depends on the composition of the pool of peptides in self-determinants. Differences in the proteins synthesized by a cell and the cell as well as the properties of the nominal peptide itseifC The absence of a competing peptide m a cell hence peptide display among individual tissues, may be lineage may allow the presentation of a determinant accentuated by the presence of cytokines. Radical which would otherwise be cryptic. Autoreactive B cells changes may be induced: for example, hepatocytes will concentrate the self antigen they recognise and increase synthesis of acute-phase reactants up to 2000bias the population of peptides displayed towards fold and shut down production of other proteins, including albumin and transferrin, within several hours those derived from the specific protein ~. It is well established that intracellular proteins, as after induction by IL-1 and IL-644. Similar shifts in well as those derived from the external milieu, can be protein synthesis are induced in many cell types by presented very efficiently on MHC class II in addition IFN-y~s and mediators such as oxygen radicals which to MHC class 13s'-~9.The display of determinants will induce the heat shock protein (hsp) response. Hsps vary depending on whether the protein is intraceilular can have a direct effect on antigen presentation: for or extracellular. For example, it has been shown that example, PBP72/74, a member of the hsp70 family, the same viral protein induces a class II restricted facilitates peptide loading onto MHC 46. ~mportantly, T-cell response to different determinants when the pro- heat shock has been shown to result in efficient presentein was produced endogenously in comparison to tation of an otherwise cryptic determinant from an admir.istration from an exogenous s o u r c e 4°'41. intracellular protein4L Exposure of APC to cytokines in chronically Although it is unclear if class II expression can be induced in oligodendrocytes which synthesize MBP in inflamed tissues will lead to increased expression of the CNS, there is evidence that presentation of en- class 11 molecules, potentially augmenting the number dogenously produced autoantigen on activated thyroid of rare MHC-peptide iigands above the critical threshold epithelia, hepatocytes and pancreatic 13 cells, does (approximately 50-200 complexes per cell) for

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viewpoint stimulation of specific T lymphocytes 48. Also, activated APC are known to express higher levels of accessory a,u adhesion molecules which lower the threshold for T-cell activation. Cytokine-induced expression of adhesion molecules occurs not only on 'professional' APC but also on other MHC ll-expressing cells suL.h as thyroid epithelia 49. All these events may enhance antigen presentation in general, but also could have a qualitative effect on peptide display. In particular, IFN-y may selectively induce some cellular proteases involved with the processing of endocytosed proteins (Cathepsin D) and proteases involved in degrading endogenously synthesised proteins (proteasome system) before their association with MHC s°-s3. While the mechanisms discussed above appear to be suited to the amplification and perpetuation of the autoimmune condition, infections can be critical in initiating the autoimmune response. Thus, microorganisms can either (a) prime a crossreactive response or (b) induce autoimmunity as a secondary event in the absence of crossreactivity. The latter possibility includes creating a microenvironment favouring display of self-determinants in the peripheral tissues (see Table 1), eventually leading to intermolecular spreading. Such s~ond wave priming to MBP has been observed following viral infections of the CNS 28,29. While intermolecular spread is an indirect consequence of the T-cell response to the instigator, viral infection may directly impact the display of self peptides on the cell. Many viruses induce dramatic shifts in protein synthesis within the infected cell so that they can increase the synthesis of their own substituents as well as cellular proteins required for this process: other syntheses are shut down. The overall 'new world order' provides a chance for the display of otherwise rare determinants. Changes in processing and presentation, such as those listed in Table 1, which lead to increases or decreases in the concentration of specific self-peptides available to bind MHC, will alter the hierarchy of dominant and cryptic determinants. A peptide which is cryptic during tolerance induction in the thymus can become a dominant determinant under 'special' conditions in the periphery and induce a self-reactive T-cell response. This would explain the data in MS where the frequency of in vivo primed T cells recognizing MBP peptides is higher than that for T cells which can respond to native MBP presented by peripheral blood mononuclear celis (Ref. 24 and Sriram, S., pers. commun.). However, induction of reactivity to cryptic determinants and changes in the expressed T-cell repertoire over time appears to be confined to certain circumstances. For example, no determinant spreading is observed in response to the foreign antigen hen eggwhite lysozyme (HEL) in any of the mouse strains tested and despite the presence of several additional determinants on the molecule2°,s4. The original specificitT pattern of the HEL-induced response persists over a prolonged period of time even after boosting (authors' unpublished results and Ref. 20). The diversification of response specificity seen with MBP presumably reflects endogenous processing and presentation occurring in a nonlymphoid organ in the context of chronic inflam-.

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mation, where many of the factors in Table 1 will apply. Anergy induction or T-cell activation Presentation of determinants not previously displayed will engage a naive T-cell population and will either lead to activation or to the induction of anergy to these determinants. Anergy may be the usual consequence of antigen presentation in nonlymphoid environments and may depend upon specific anergyinducing signals or the absence of secondary activation signals. In contrast, the initiation of autoimmune responses will require an alteration of the local signal environment or, alternatively, will result from the failure to respond appropriately to anergy-inducing signals. Such a change in the local signalling environment can be produced by the local production of cytokines, such as IFN-~ s. Surprisingly, it may not be necessary for the secondary signal to be delivered by the actual APC, but by a separate cell population altogether s6' even in the case of short range costimulatory signals such as the CD28-B7/BB1 interaction. The requirement for local upregulation of antigen presentation and expression of accessory molecules will tend to produce focal disease with clusters of activated T cells and other inflammatory cells in areas of active presentation. This would explain the characteristic observation of discrete plaques seen in chronic MS and the focal damage seen in some other autoimmune diseases. Reversing an immunostimulatory environment: a new therapeutic approach.

If autoimmune responses are highly diverse, what new therapeutic approaches will be successful? Once priming to cryptic self has occurred, a vicious cycle of tation leading to ongoing T-cell stimulation, further T-cell recruitment and determinant spreading, greater cytokine production and so forth, will result. However, this cycle of events could be broken by the manipulation of antigen presentation by anti-MHC antibodies or blocking peptides (probably directed acutely agair':t several MHC molecules), with anticytokine annbgdies, or with inhibitory cytokines, such as TGF-[3 and ~L-103°.57.58 This will regrettably involve a general level of immunosuppression and it is unclear whether or not such a treatment for autoimmunity would be permanent given the presence of a primed population of autoreactive T cells. These activated populations are the most difficult to control since they are relatively refractory even to cyclosporin s9. However, the current notion that T-cell memory is short lived in the absence of antigen suggests that if autoantigen presentation were halted, the primed repertoire would regress 6°. The ability to reverse the immunostimulatory environment and to regulate antigen presentation (hence T-cell activation), could form the basis of an effective, but non-selective, strategy for the long-term control of organ-specific autoimmunity. A better understanding of the differences between antigen presentation in nonlymphoid versus lymphoid environments and between presentation of exogenously supplied and endogenously

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viewpoint produced antigens, may allow selective regulation and avoidance of the consequence of generalized immunosuppression. Drugs could be targeted to specific organs or sites of acute inflammation which will differ from nearby tissues. Additionally, methods to convert the immunostimulatory environment in an affected organ to an anergy- or apoptosis-inducing environment could be developed. This could be achieved by using monoclonal antibodies specific for certain cytokines or accessory molecules. Thus, the overall strategy is designed to force a return to the quiescent preactivated state, thereby allowing the target orzan to cure itself. Paul V. Lehmann and Thomas Forsthuber are at the Dept of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA; Eli E. Sercarz is at the Depi of Microbiology and Molecular Genetics, University of California Los Angeles, CA 90024-1489, USA; Colin M. Dayan is at the Dept t,f Endocrinology, Chafing Cross Hospital, London W6 and Guy Gammon is at Xenova Ltd, 240 Bath Road, Slough, UK SL1 4EQ. References 1 Martin, R., McFarland, H.F. and McFarlin, D.E. (1992) Annu. Review lmmunol. 10, 153-187 2 Urban, J.L., Kumar, V., Kono, D.H., Gomez, C., Horvath, S.J., Clayton, J., Ando, D.G., Sercarz, E.E. and Hood, L. (1988) Cell 54, 577-592 3 Acha-Orbea, H., Mitchell, D.J., Timmermann, L., Wraith, D.C., Tausch, G.S., Waldor, M.K., Zamvii, S.S., McDevitt, H.O. and Steinman, L. (1988) Cell 54, 263-273 40whashi, M. and Heber-Katz, E. (1988)]. Exp. Med. 168, 2153-2164 5 Ota, K., Matsui, M., Milford, E.L., Mackin, G.A., Weiner, H.L. and Hailer, D.A. (1990) Nature 346, 183-!87 60ksenberg, J.R., Stuart, S., Begovich, A.B., Bell, R.B., Erlich, H.A., Steinman, L. and Bernard, C.C. (1990) Nature 345, 344-346 7 Kotzin, B.L., Karuturi, S.; Chou, Y.K., Lafferty, J., Forrester, J.M., Better, M., Nedwin, G.E., Offner, H. and Vandenbark, A.A. (1991) Proc. Natl Acad. Sci. USA 88, 9161-9165 8 Giegerich, G., Pette, M., Meinl, E., Epplen, J.T., Wekerle, H. and Hinkkanen, A. (1992) Eur. J. hnmunol. 22, 753-758 9 Martin, R., Utz, U., Coligan, J.E., Richert, J.R., Flerlage, M., Robinson, E., Stone, R., Biddison, W.E., McFarlin, D.E. and McFarland, H.F. (1992)J. lmmunol. 148, 1359-1366 10 Pette, M., Fujita, K., Wilkinson, D., Aitmann, D.M., Trowsdale, J., Giegerich, G., Hinkkanen, A., Epplen, J.T., Kappos, L. and Wekerle, H. (1990) Proc. Natl Acad. Sci. USA 87, 7968-7972 11 Dayan, C.M., Londei, M., Corcoran, A.E., GrubeckLoebenst.~in, B., James, R.F.L., Rapoport, B. and Feldmann, M. (1991) Proc. Natl Acad. Sci. USA 88, 7415-7419 12 Davies, T.F., Martin, A., Concepcion, E.S., Graves, P., Cohen, L. and Ben-Nun, A. (1991) New Eng. J. Med. 325, 238-244 13 Harcourt, G.C., Sommer, N., Rothbard, J.B., Wilcox, H.N.A. and Newsom-Davis, J.A. (1988)J. Clin. hwest. 82, 1295-1300 14 Zhang, Y., Schleup, M., Fruitiger, S., Hughes, G.J., Jeannet, M., Steck, A. and Barkas, T. (1990) Eur. J. lmmunol. 20, 2577-2583 15 Kontiainen, S., Toomath, R., L.,wder, J. and Feldmann, M. (1991) CIm. Exp. lmmunol. 83, 347-351

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47 Michalek, M.T., Benacerraf, B. and Rock, K.L. (1992)

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48 Demotz, S., Grey, H.M. and Sette, A. (1990) Science 249, 1028-1030 49 Zheng, R.Q.H., Abney, E., Grubeck-Loebenstein, B. et al. (1991) J. Autoimmun. 3, 727-736 50 Rossman, M.D., Maida, B.T.and Douglas, S.D. (1990) Cell. lmmunoL 126, 268-277 51 Kelly,A., Powis, S.H., Giynne, R., Radley, E., Beck, S. and Trowsdale, J. (1991) Nature 353, 667-668 52 Yang, Y., Waters, J.B., Fruh, K. and Peterson, P.A. (1992) Proc. Natl Acad. Sci. USA 89, 4928-4932 53 Monaco, J.J. (1992) ImmunoL Today 13, 173-179 54 Gammon, G., Geysen, H.M., Apple, R.J., Pickett, E., Palmer, M., Ametani, A. and Sercarz, E.E. (1991)J. Exp.

How do T-cell receptors, MHC molecules and superantigens get together? David L. Woodland and Marcia A. Blackman The current model of superantigen activity assumes that the superantigen simultaneously binds to both the MHC molecule on the presenting cell and the V~ element of the TCR, resulting in crosslinking of both molecules and subsequent activation of the T cell. Here, David Woodland and Marcia Blackman discuss the concept that there is an additional interaction between the TCR and MHC molecule during superantigen engagement and the significant impact this has on superantigen ec, D , - ; ( ; , - ; ~ . . . . .

.4 4 . . ~ , . - ~ ; . , ~ ,

T-cell recognition of superantigcn is distinguished from recognition of conventional peptide antigen by two fundamental properties. First, although superantigens depend on major histocompatibility complex (MHC) class lI molecules for functional expression, T-cell recognition of superantigen-MHC complexes is not classically MHC restricted. Thus, a single superantigen can be recognized in the context of multiple class II alleles and isotypes, including xenogeneic class II molecules. However, individual class II molecules vary in their effectiveness at presenting superantigens to T cells and can be ordered into a hierarchy; in mice there is a well-established hierarchy for the presentation of endogenous retroviral superantigens, where H-2k,H 2d>H-2b>H-2q. Second, T-cell specificity for superantigen is determined by the V~ element, essentially independent of other components of the T-cell receptor (TCR). This central role of V~ explains the potency of superantigens with respect to T-cell activation because there are only a small number of VI~genes that are each expressed at high frequency among T cells (reviewed in Refs 1-5). These two basic characteristics have been incorporated into a simple model in which the superantigen

activates the T-cell by directly crosslinking the MHC class II molecule on the presenting cell and the TCR Vi3 element on the T cell (fig. 1). Several lines of evidence support this model. Studies with bacterial guperantigens have shown direct binding to solventexposed regions of the MHC class II molecule, outside of the peptide-binding groove 6.-,~. The hierarchy of superantigen presentation by individual MHC class II molecules can be explained in terms of different binding affinities between bacterial superantigens and class II alleles anci isotypes ~-.4. In addition, mutational analysis of TCR 43-chains specific for both bacterial and viral superantigens, and peptide inhibition studies (bacterial superantigens), have identified a superantigen binding site on the V~ element, which, based on structural similarities between TCR and immunoglobulin genes, is predicted to lie on a solventexposed face of the TCR distant to the classical antigen-MHC binding site *s-~9. Also consistent with this model is the observation that the functional presentation of bacterial superantigens is not dependent on antigen processing 2°-22, although there is recent evidence that viral superantigens may undergo processing 2-3.

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Voi 14 No. 5 1993