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The Journal of Immunology, 1998, 161: 1705-1709.
Copyright © 1998 by The American Association of Immunologists

Termination of Peripheral Tolerance to a T Cell Epitope by Heteroclitic Antigen Analogues1

Ulrich Zügel*, Rongfang Wang*, Grace Shih*, Alessandro Sette{dagger}, Jeff Alexander{dagger} and Howard M. Grey2,*

* La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; and {dagger} Cytel Corporation, San Diego, CA 92121


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Treating mice with an immunodominant T cell epitope from moth cytochrome c (MCC88–103) can induce T cell unresponsiveness under certain conditions of administration. In this report, we determined whether T cell tolerance to MCC88–103 in adult animals can be overcome by immunization with cross-reactive analogues of the tolerizing Ag. A panel of analogues of the tolerogen were tested for their capacity to terminate the tolerant state following in vivo immunization. As analyzed by their stimulatory capacity for a representative MCC88–103-specific T cell clone, this panel covered a wide range of cross-reactivity, including nonantigenic, antagonistic, weakly, and strongly antigenic peptides. Interestingly, only heteroclitic analogues, as measured in vitro by their enhanced antigenicity for the T cell clone that was specific for MCC88–103, were capable of breaking tolerance. Thus, an immune response to the cross-reactive, heteroclitic analogues of tolerized self Ags may represent a mechanism by which Ag molecular mimicry operates.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
According to the concept of antigenic molecular mimicry, sequence similarity between a foreign pathogen and a self Ag leads to the induction of an immune response to the foreign Ag that cross-reacts with the self Ag. There are two possible explanations as to how such a foreign Ag might induce an immune response to a self Ag. First, the specific self peptide that shares homology with the foreign Ag may never have induced a state of self tolerance (1, 2, 3). Normally, no autoimmunity to this epitope is observed, because the epitope is not expressed on a potent APC or because it is inefficiently processed and displayed on the surface of an APC as a result of its structure or the structure of flanking regions of the protein from which it is derived (i.e., it is a cryptic epitope) (4, 5). In the course of the immune response to the foreign Ag, the cross-reactive, nonself epitope becomes effectively processed by a professional APC and induces the latent immune response to the cross-reactive self epitope.

The second possible mechanism by which a cross-reactive epitope on a foreign Ag may give rise to an antiself response involves potentially immunodominant T cell epitopes that have actively induced a state of self tolerance. In this case, central and/or peripheral tolerance to the epitope exists in the host. Due to the structural characteristics of the foreign cross-reactive epitope, a subset of untolerized T cells (perhaps with too low an affinity to have been tolerized by the self epitope) or previously anergized T cells become activated by the foreign epitope and can now recognize the self epitope and initiate the autoimmune process (3, 6, 7).

In this study, we have investigated this second explanation for antigenic mimicry. The tolerant state induced to the dominant I-Ek-restricted epitope of moth cytochrome c (MCC)3, MCC88–103, was studied as a model system. The immune response to this peptide has been well-characterized by several investigators (8, 9, 10, 11, 12, 13). One of the advantages of this epitope is that it generates a rather restricted T cell response in H-2k animals; this response is dominated by TCRs that use V{alpha}11 and Vß3 (14, 15, 16), and although different T cell clones vary somewhat in their fine specificity, the major T cell contact residues appear to be conserved. Thus, information on the relative immunogenicity of MCC88–103 analogues that is gained at the clonal level may be pertinent for the polyclonal in vivo response as well.

Data are presented that indicate that tolerance to MCC can be terminated by certain cross-reactive Ags. Strikingly, those peptides capable of breaking tolerance were all characterized as heteroclitic Ags, in that they were more potent stimulators of the MCC88–103-specific T cell clone than the parental Ag.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Immunization protocol

For tolerance induction, 8- to 12-wk-old B10.A mice (The Jackson Laboratory, Bar Harbor, ME) were injected i.p. with 300 µg of MCC88–103 in IFA (Pierce, Rockford, IL). After 10 days, tolerized and untolerized mice were immunized s.c. at the base of the tail with 2 µg of MCC88–103 or analogues of MCC88–103 in CFA (Difco, Detroit, MI). After 10 days, isolated lymph node cells (LNCs) were stimulated with MCC88–103 and analyzed for proliferative activity and cytokine secretion.

Proliferation assays

The AD10 pigeon cytochrome c I-Ek-restricted clone was kindly provided by Dr. S. Hedrick (University of California, San Diego, CA), and AD10 cells were cultured as described previously (17). LNCs (paraaortic and inguinal) were plated at 2.5 x 105 cells along with 2.5 x 105 irradiated (3000 rad) syngeneic splenocytes and then stimulated with the MCC88–103 epitope or with MCC analogues as indicated. After 72 h, the cultures were pulsed for another 18 h with 1 µCi of [3H]thymidine and analyzed by beta-plate scintography.

Cytokine assays

For cytokine analysis, supernatants from the cultures that had been established to measure the proliferative response were removed after 24 h and assayed for IL-2, removed after 48 h and assayed for IL-4 and IL-10, or removed after 72 h and assayed for IFN-{gamma}. The IL-2 was measured by a bioassay using the CTLL-2 cell line. IL-4, IL-10, and IFN-{gamma} were assayed by ELISA according to the instructions provided by the manufacturer of the reagents (PharMingen, San Diego, CA). The sensitivities of the ELISA assays were as follows: IFN-{gamma}, 100 pg/ml; IL-4, 50 pg/ml; and IL-10, 50 pg/ml.

I-Ek binding assay

Peptides were analyzed for their ability to bind to purified I-Ek molecules as described previously (18). The binding capacity is reported as the concentration of peptide required to obtain a 50% inhibition (IC50) of binding of the radiolabeled ligand. Peptides were synthesized as described previously (17) and authenticated by mass spectrometry.

Calculation of data

To obtain a quantitative estimation of the extent to which tolerance was terminated following immunization with analogue peptides, the data from proliferative and cytokine assays were pooled from the three highest concentrations of Ag and used in the following calculation to determine the percent termination of tolerance: 100 x ([MCC-tolerized, analogue-immunized - MCC-tolerized, MCC-immunized]/[untolerized, MCC-immunized - MCC-tolerized, MCC-immunized]).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Characterization of tolerance to MCC88–103

To determine the efficiency of tolerance induction, 10 days after an i.p. injection of 300 µg of MCC88–103 in IFA, animals were immunized s.c. with the same peptide in CFA; 10 days later, LNCs were stimulated in vitro with MCC88–103, and proliferative and cytokine responses were subsequently measured. The cytokine responses from the nontolerized animals indicated that IFN-{gamma} and IL-2 were the predominant cytokines that were made to this Ag; no detectable IL-4 or IL-10 was observed (Fig. 1Go, and data not shown). The proliferative response of cells from tolerized animals was drastically diminished to a level that was 5 to 15% of the maximum response that was observed with the cell cultures from untolerized animals. Also, an almost complete loss of both IL-2 and IFN-{gamma} production was observed; responses in the range of 0 to 5% of the untolerized control group were obtained in the multiple experiments performed. Of particular interest is the observation that there was no IL-4 or IL-10 detected in the cultures that were derived from tolerized animals as analyzed by ELISA or the more sensitive enzyme-linked immunospot assay (data not shown). Thus, immune deviation to a Th2-like response was not responsible for the decrease in the production of the Th1 cytokines or in the proliferative response (19, 20, 21).



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  		FIGURE 1. Induction of tolerance to MCC88–103. B10.A mice were tolerized with 300 µg of MCC88–103 in IFA i.p. After 10 days, tolerized and nontolerized mice were immunized s.c. with 2 µg of MCC88–103 in CFA. LNCs were collected at 10 days postimmunization and stimulated with the indicated concentrations of MCC88–103. LNCs from tolerized ({diamond}) and untolerized ({blacksquare}) mice were tested in a proliferation assay (A). For cytokine analysis, 50 µl of supernatants from the cultures that had been established to measure the proliferative response were removed and tested for IFN-{gamma} (B) and IL-2 (C). The data are representative of three independent experiments.

 
Choice of MCC88–103 analogues to test for their capacity to terminate the tolerant state to MCC88–103

A set of 15 peptides was selected to determine their capacity to break tolerance to MCC88–103. The peptides were chosen on the basis of two criteria. First, all of these peptides possessed a relatively high binding capacity for I-Ek, possessing IC50 values of <200 nM, which is a level that has been determined previously to be sufficient for a peptide to be potentially immunogenic (22). Second, the peptides represented a broad range of antigenicity for a cytochrome-specific T cell clone, AD10. It has been demonstrated that this clone is fairly typical of the cytochrome c-specific response that is generated in H-2k mice; i.e., it contains a Vß3/V{alpha}11 TCR that recognizes K99 and T102 as dominant TCR contact residues on the MCC peptide (12, 13, 23). Thus, information on the relative immunogenicity of MCC88–103 analogues that is gained at the clonal level may be pertinent for the polyclonal in vivo response as well. As shown in Table IGo, the panel included nonantigenic peptides, TCR antagonistic peptides, and antigenic peptides, which varied from weak to very strong.


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  		Table I. I-Ek binding and T cell stimulatory capacity of MCC88-103 analogues

 
Capacity of MCC88–103 analogues to terminate tolerance to MCC88–103

In most instances, when tolerized mice were immunized with the Ag analogues listed in Table IGo, no greater response to MCC88–103 was observed than that obtained following immunization with the tolerogen. Although tolerance was not broken, a significant response against the immunizing analogue was obtained in all instances (stimulation indices of 2–10 in tolerized animals and 3–14 in nontolerized animals). A representative example of the failure to respond to MCC88–103 is shown in Figure 2GoA. The proliferative responses of LNCs were in the range of 10% or less of that seen with the untolerized control animals, with little or no cytokine production being detected.



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  		FIGURE 2. Capacity of Ag analogues to terminate tolerance. The analogue peptides T102S (A) and L98A (B) were used to immunize mice that had been tolerized previously to MCC88–103. LNCs from nontolerized mice ({blacksquare}), tolerized and MCC88–103-immunized mice ({diamond}), and tolerized and MCC analogue-immunized mice ({blacktriangleup} = T102S; {diamondsuit} = L98A) were analyzed for their proliferative activity and for secretion of IL-2 and IFN-{gamma}. The data are representative of three independent experiments. No IL-4 or IL-10 production was detected (data not shown).

 
In striking contrast to these negative results, a few peptides were very efficient in terminating tolerance. The data from one such peptide, L98A, are shown in Figure 2GoB. Cells from animals that were first tolerized to MCC88–103 and then immunized with L98A gave a peak proliferative response to MCC88–103 that was ~75% of that of the untolerized controls. Also, a virtually complete reconstitution of the IFN-{gamma} response and a partial reconstitution of IL-2 production was achieved. Cells from animals that had been tolerized and immunized with MCC88–103 were included and served as tolerized control cultures.

A summary of all data is shown in Table IIGo. Three peptides were consistently successful in inducing a significant immune response to the MCC88–103 peptide following the induction of tolerance to that peptide. Peptide 4 (Y97F) was the least efficient; this peptide restored the proliferative response to 25% of normal but had no effect on cytokine production. The two most potent analogues in terminating tolerance had a substitution at position 98 (L to A (peptide 7) and L to F (peptide 6)). None of the other 12 peptides studied had any significant effect on the tolerant state to MCC88–103. In comparing the data obtained in Tables I and II, it is striking that the peptides that were capable of terminating tolerance to MCC88–103 were better Ags than the wild-type MCC88–103 for the AD10 clone; i.e., they were heteroclitic (24, 25, 26, 27).


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  		Table II. Summary of the capacity of MCC88-103 analogs to terminate tolerance to MCC88-103

 
It is to be noted that immunizations in CFA with all the Ag analogues were also performed with a higher dose (20 µg) than the 2 µg used in the experiments shown in Table IIGo. Similar results were obtained at both doses. Only the three peptides capable of breaking tolerance when the 2-µg immunizing dose was used were also able to break tolerance to MCC88–103 using the higher dose. Also, immunization with higher doses of MCC88–103 (up to 100 µg/ml) did not lead to any decrease in the state of tolerance in any instance.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Here, we have demonstrated that T cell tolerance to an immunodominant T cell epitope that is induced in adult animals can be overcome by immunization with heteroclitic cross-reactive peptide analogues of the tolerizing Ag. The striking observation was that only heteroclitic analogues, as measured by their enhanced antigenicity for the AD10 clone compared with MCC88–103, were capable of breaking tolerance to MCC88–103. The heteroclitic nature of these analogues was not restricted to the AD10 clone; rather, it was also observed with several other MCC88–103- specific T cell clones and could be detected with a bulk response using T cells from MCC88–103-immunized mice when limiting Ag concentrations were used.

With respect to heteroclitic reactivity, there would appear to be two potential explanations as to how an Ag analogue with the same affinity for MHC as the Ag may be a more effective Ag than the immunogen that induced the original response. First, the heteroclitic Ag may bind with higher affinity to the TCR due to the replacement of a TCR contact residue with a closely related amino acid that is capable of even stronger interactions with the TCR. This is probably the mechanism for the heteroclicity of the Y97F analogue, since Y97 has been characterized as a subdominant TCR contact residue by ourselves and others (12, 13).

The second explanation for heteroclicity is the substitution of a residue that is not a TCR contact residue in and of itself but is somehow detrimental to the interaction between peptide and TCR when it is present. On the basis that multiple substitutions at position L98 were tolerated with respect to MHC binding and T cell recognition (Table IGo, and H. M. Grey, unpublished observations), this residue was designated as a "spacer" residue, which is not directly involved in MHC or TCR contact. However, a recent crystallographic analysis of the peptide/I-Ek complex indicates that L98 should be an MHC contact residue (28). Thus, the most likely explanation for the heteroclicity of MCC88–103 analogues with L98 substitutions is that changes in the way residues at this position engage the MHC alter the orientation of the TCR contact residues, resulting in an enhancement of the binding of these analogues to the TCR. A similar effect of a change in an MHC contact residue on TCR interaction has been observed with another I-Ek-restricted response (29, 30). This type of heteroclicity may be ideally suited to terminate the tolerant state to an Ag; since the TCR contact residues are identical with the tolerized Ag, most of the T cell repertoire induced to the analogue should be capable of reacting with the tolerized Ag as well.

What is the mechanism by which tolerance was terminated with the heteroclitic Ags? Mechanisms to be considered include immune deviation, reversal of anergy, and the activation of nontolerized cross-reactive clones of T cells. There was no evidence that tolerance induction led to a switch from a Th1 to a Th2 response either before or after tolerance termination, thus eliminating immune deviation as a factor in this system. With respect to the activation of previously anergized clones, there are no data supporting or contradicting this possibility. We are currently attempting to evaluate this idea by inducing tolerance in a TCR-transgenic population of T cells to determine whether tolerance can be reversed at the clonal level.

There are data, however, that support the hypothesis that the breaking of tolerance involves the stimulation of low affinity, nontolerized T cell clones. As illustrated in Figure 2Go, cells from previously tolerized animals required 10- to 100-fold more Ag to be comparably stimulated by MCC88–103 than did cells from nontolerized animals. These findings are compatible with the concept that T cell clones with too low an affinity for MCC88–103 to be tolerized were stimulated by the heteroclitic analogues. In further support of this concept is the finding that there appears to be a somewhat different repertoire of T cells stimulated by the L98A analogue compared with MCC88–103. An analysis of short-term lines for Vß3 and V{alpha}11 usage indicated that L98A elicited fewer Vß3+/V{alpha}11+ cells than MCC88–103 (13 vs 35%) and more Vß3-/V{alpha}11+ cells (38 vs 15%). We propose that these T cells with low affinity for MCC88–103 (perhaps Vß3-/V{alpha}11+) become responsive to secondary stimulation with the tolerogen following activation by the heteroclitic Ag. We are attempting to obtain further proof of this model by analyzing MCC88–103-reactive T cell clones that have been derived from previously tolerized animals immunized with the heteroclitic analogues.

Finally, these data not only directly demonstrate one mechanism by which molecular mimicry by a foreign Ag may function in the termination of self tolerance and the induction of autoimmunity, but they may also be relevant to therapeutic vaccine design in situations in which persistent Ag exposure associated with malignant tumors or chronic infectious disease leads to a state of tolerance. In these instances, immunization with heteroclitic analogues of T cell epitopes may be a more effective strategy than the use of natural determinants.


   Acknowledgments
 
We thank Scott Southwood, Dung Huynh, and Mohammed Ullah for expert technical assistance and Joyce Joseph for assistance in the preparation of the manuscript.


   Footnotes
 
1 This study was supported by Grant AI-18634 from the National Institutes of Health (to H.M.G.) and a postdoctoral fellowship from the Deutschen Akademischen Austauschdienst (DAAD) and the Deutsche Forschungsgemeinschaft (DFG) (to U.Z.). This is publication number 180 from the La Jolla Institute for Allergy and Immunology. Back

2 Address correspondence and reprint requests to Dr. Howard M. Grey, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121. Back

3 Abbreviations used in this paper: MCC, moth cytochrome c; LNC, lymph node cell; IC50, 50% inhibiting concentration. Back

Received for publication August 19, 1997. Accepted for publication April 14, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Cibotti, R., J. M. Kanellopoulos, J. P. Cabaniols, O. Halle-Panenko, K. Kosmatopoulos, E. Sercarz, P. Kourilsky. 1992. Tolerance to a self-protein involves its immunodominant but does not involve its subdominant determinants. Proc. Natl. Acad. Sci. USA 89:416.[Abstract/Free Full Text]
  2. Mamula, J.. 1993. The inability to process a self-peptide allows autoreactive T cells to escape tolerance. J. Exp. Med. 177:567.[Abstract/Free Full Text]
  3. Liu, G. Y., P. J. Fairchild, R. M. Smith, J. R. Prowle, D. Kioussis, D. C. Wraith. 1995. Low avidity recognition of self-antigen by T cells permits escape from central tolerance. Immunity 3:407.[Medline]
  4. Brett, S. J., K. B. Cease, J. A. Berzofsky. 1988. Influences of antigen processing on the expression of the T cell repertoire: evidence for MHC-specific hindering structures on the products of processing. J. Exp. Med. 168:357.[Abstract/Free Full Text]
  5. Mougdil, K. D., I. S. Grewal, P. E. Jensen, E. E. Sercarz. 1996. Unresponsiveness to self-peptide of mouse lysozyme owing to hindrance of TCR-major histocompatibility complex/peptide interaction caused by flanking epitopic residues. J. Exp. Med. 183:535.[Abstract/Free Full Text]
  6. Tam, C., E. V. Fedoseyeva, M. Moskalenko, M. R. Garovoy, G. Benichou. 1996. T cell tolerance is influenced by concomitant T cell recognition of cross-reactive self-peptides. J. Immunol. 156:3765.[Abstract]
  7. Cerasoli, D. M., J. McGrath, S. R. Carding, F. F. Shih, B. B. Knowles, A. J. Caton. 1995. Low avidity recognition of a class II-restricted neo-self peptide by virus-specific T cells. Int. Immunol. 7:935.[Abstract/Free Full Text]
  8. Oehen, S., L. Feng, Y. Xia, C. D. Surh, S. M. Hedrick. 1996. Antigen compartmentation and T helper cell tolerance induction. J. Exp. Med. 183:2617.[Abstract/Free Full Text]
  9. Fox, B. S., C. Chen, E. Fraga, E. C. A. French, B. Singh, R. H. Schwartz. 1987. Functionally distinct agretopic and epitope sites: analysis of the dominant T cell determinant of moth and pigeon cytochromes c with the use of synthetic peptide antigens. J. Immunol. 139:1578.[Abstract]
  10. Bhayani, H., Y. Paterson. 1989. Analysis of peptide binding patterns in different major histocompatibility complex TCR complexes using cytochrome c-specific T cell hybridomas. J. Exp. Med. 170:1609.[Abstract/Free Full Text]
  11. Sorger, S. B., Y. Paterson, P. J. Fink, S. M. Hedrick. 1990. TCR junctional regions and the MHC molecule affect the recognition of antigenic peptides by T cell clones. J. Immunol. 144:1127.[Abstract]
  12. Reay, P. A., R. M. Kanor, M. M. Davis. 1994. Use of global amino acid replacements to define the requirements for MHC binding and T cell recognition of moth cytochrome c (93–103). J. Immunol. 152:3946.[Abstract]
  13. Page, D. M., J. Alexander, K. Snoke, E. Appella, A. Sette, S. M. Hedrick, H. M. Grey. 1994. Negative selection of CD4+ CD8- thymocytes by T-cell receptor peptide antagonists. Proc. Natl. Acad. Sci. USA 91:4057.[Abstract/Free Full Text]
  14. Fink, P. J., L. A. Mathis, D. L. McElligot, M. Bookman, S. M. Hedrick. 1986. Correlations between T-cell specificity and the structure of the antigen receptor. Nature 321:219.[Medline]
  15. Winoto, A., J. L. Urban, N. C. Lan, J. Goverman, L. Hood, D. Hansburg. 1986. Permanent use of V{alpha} gene segment in mouse T-cell receptors for cytochrome c. Nature 324:679.[Medline]
  16. Nakano, N., R. Rooke, C. Benoist, D. Mathis. 1997. Positive selection of T cells induced by viral delivery of neopeptides to the thymus. Science 275:678.[Abstract/Free Full Text]
  17. La Face, D. M., C. Couture, K. Anderson, G. Shih, J. Alexander, A. Sette, T. Mustelin, A. Altman, H. M. Grey. 1997. Differential T cell signaling induced by antagonist peptide-MHC complexes and the associated phenotypic responses. J. Immunol. 158:2057.[Abstract]
  18. Sette, A., S. Southwood, D. O’Sullivan, F. C. A. Gaeta, J. Sidney, H. M. Grey. 1992. Effect of pH on class II-peptide interactions. J. Immunol. 148:844.[Abstract]
  19. Nicholson, L. B., J. M. Greer, R. A. Sobel, M. B. Lees, V. J. Kuchroo. 1995. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 3:397.[Medline]
  20. Constant, S., C. Pfeiffer, A. Woodward, T. Pasqualini, K. Bottomly. 1995. Extent of TCR ligation can determine the functional differentiation of naive CD4+ T cells. J. Exp. Med. 182:1591.[Abstract/Free Full Text]
  21. Degermann, S., E. Pria, L. Adorini. 1996. Soluble protein but not peptide administration diverts the immune response of a clonal CD4+ T cell population to the Th2 cell pathway. J. Immunol. 157:3260.[Abstract]
  22. Schaeffer, E. B., A. Sette, D. L. Johnson, M. C. Bekoff, J. A. Smith, H. M. Grey, S. Buus. 1989. Relative contribution of "determinant selection" and "holes in the T cell repertoire" to T cell responses. Proc. Natl. Acad. Sci. USA 86:4649.[Abstract/Free Full Text]
  23. Hedrick, S. M., I. Engel, P. J. Fink, M.-L. Hsu, D. Hansburg, L. A. Mathis. 1988. Selection of amino acid sequences in the ß-chain of T cell antigen receptor. Science 239:1541.[Abstract/Free Full Text]
  24. England, R. D., M. C. Kullberg, J. L. Cornette, J. A. Berzofsky. 1995. Molecular analysis of a heteroclitic T cell response to the immunodominant epitope of sperm whale myoglobin. J. Immunol. 155:4295.[Abstract]
  25. Michaëlsson, E., M. Andersson, A. Engström, R. Holmdahl. 1992. Identification of an immunodominant type-II collagen peptide recognized by T cells in H-2q mice: self tolerance at the level of determinant selection. Eur. J. Immunol. 22:1819.[Medline]
  26. Baumhüter, S., C. J. A. Wallace, A. E. I. Proudfoot, C. Bron, G. Corradin. 1987. Multiple T cell antigenic determinants identified within a limited region of the horse cytochrome c molecule. Eur. J. Immunol. 17:651.[Medline]
  27. Wraith, D., D. E. Smilek, D. J. Mitchell, L. Steinmann, H. O. McDevitt. 1989. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell 59:247.[Medline]
  28. Fremont, D. H., W. A. Hendrickson, P. Marrack, J. Kappler. 1996. Structures of an MHC class II molecule with covalently bound single peptides. Science 272:1001.[Abstract]
  29. Kersh, G. J., P. M. Allen. 1996. Structural basis for T cell recognition of altered peptide ligands: single TCR can productively recognize a large continuum of related ligands. J. Exp. Med. 184:1259.[Abstract/Free Full Text]
  30. Evavold, B. D., S. G. Williams, B. L. Hsu, S. Buus, P. M. Allen. 1992. Complete dissection of the Hb(64–76) determinant using Th1, Th2 clones, and T cell hybridomas. J. Immunol. 148:347.[Abstract]
  31. De Magistris, M. T., J. Alexander, M. Coggeshall, A. Altman, F. C. A. Gaeta, H. M. Grey, A. Sette. 1992. Antigen analog-major histocompatibility complexes act as antagonists of the TCR. Cell 68:625.[Medline]



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J. Immunol., January 1, 2002; 168(1): 283 - 289.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
K. E. de Visser, T. A. Cordaro, H. W. H. G. Kessels, F. H. Tirion, T. N. M. Schumacher, and A. M. Kruisbeek
Low-Avidity Self-Specific T Cells Display a Pronounced Expansion Defect That Can Be Overcome by Altered Peptide Ligands
J. Immunol., October 1, 2001; 167(7): 3818 - 3828.
[Abstract] [Full Text] [PDF]

Home page
 J. Exp. Med.Home page
S. Tangri, G. Y. Ishioka, X. Huang, J. Sidney, S. Southwood, J. Fikes, and A. Sette
Structural Features of Peptide Analogs of Human Histocompatibility Leukocyte Antigen Class I Epitopes that Are More Potent and Immunogenic than Wild-Type Peptide
J. Exp. Med., September 17, 2001; 194(6): 833 - 846.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
L. Fong, Y. Hou, A. Rivas, C. Benike, A. Yuen, G. A. Fisher, M. M. Davis, and E. G. Engleman
Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy
PNAS, June 20, 2001; (2001) 141226398.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. K. Joshi, P. R. Suresh, and V. S. Chauhan
Flexibility in MHC and TCR Recognition: Degenerate Specificity at the T Cell Level in the Recognition of Promiscuous Th Epitopes Exhibiting No Primary Sequence Homology
J. Immunol., June 1, 2001; 166(11): 6693 - 6703.
[Abstract] [Full Text] [PDF]

Home page
 J. Exp. Med.Home page
S. M. Anderton, C. G. Radu, P. A. Lowrey, E. S. Ward, and D. C. Wraith
Negative Selection during the Peripheral Immune Response to Antigen
J. Exp. Med., December 27, 2000; 193(1): 1 - 12.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. Lu and E. Celis
Use of Two Predictive Algorithms of the World Wide Web for the Identification of Tumor-reactive T-Cell Epitopes
Cancer Res., September 1, 2000; 60(18): 5223 - 5227.
[Abstract] [Full Text]

Home page
 J. Virol.Home page
L. Bouhdoud, P. Villain, A. Merzouki, M. Arella, and C. Couture
T-Cell Receptor-Mediated Anergy of a Human Immunodeficiency Virus (HIV) gp120-Specific CD4+ Cytotoxic T-Cell Clone, Induced by a Natural HIV Type 1 Variant Peptide
J. Virol., March 1, 2000; 74(5): 2121 - 2130.
[Abstract] [Full Text]

Home page
 J. Exp. Med.Home page
R. Wang, Y. Wang-Zhu, C. R. Gabaglia, K. Kimachi, and H. M. Grey
The Stimulation of Low-Affinity, Nontolerized Clones by Heteroclitic Antigen Analogues Causes the Breaking of Tolerance Established to an Immunodominant T Cell Epitope
J. Exp. Med., October 4, 1999; 190(7): 983 - 994.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
L. Fong, Y. Hou, A. Rivas, C. Benike, A. Yuen, G. A. Fisher, M. M. Davis, and E. G. Engleman
Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy
PNAS, July 17, 2001; 98(15): 8809 - 8814.
[Abstract] [Full Text] [PDF]

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