Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Apr 1;183(4):1311–1321. doi: 10.1084/jem.183.4.1311

Endogenous altered peptide ligands can affect peripheral T cell responses

PMCID: PMC2192490  PMID: 8666889

Abstract

T cells potentially encounter a large number of endogenous self- peptide/MHC ligands in the thymus and the periphery. These endogenous ligands are critical to both positive and negative selection in the thymus; however, their effect on peripheral T cells has not been directly ascertained. Using the murine allelic Hbd (64-76)/I-Ek self- antigen model, we have previously identified altered peptide ligands (APLs) which are able to stimulate some but not all TCR-mediated effector functions. To determine directly the effect of endogenously synthesized APL/MHC complexes on peripheral T cells, we used a TCR transgenic mouse which had reversed our normal antigen system, with Ser69 peptide now being the agonist and Hbd(64-76) being the APL. In this report, we show that the constitutive level of endogenous Hbd(64- 76)/I-Ek complexes presented by APCs in vivo is too low to affect the response of Ser69 reactive T cells. However, by increasing the number of Hbd(64-76)/I-Ek complexes expressed by the APCs, TCR antagonism is observed for both primary T cells and T cell hybridomas. In addition, the level of the CD4 coreceptor expressed on T cells and T cell hybridomas. In addition, the level of the CD4 coreceptor expressed on T cells changes the response pattern to endogenously presented Hbd(64- 76)/I-Ek ligand. These findings demonstrate that T cells are selected to ignore the constitutive levels of endogenous complexes they encounter in the periphery. T cell responses can be affected by endogenous APLs in the periphery under limited but attainable circumstances which change the efficacy of the TCR/ligand interaction. Thus, endogenous APLs play a role in both the selection of T cells in the thymus and the responses of peripheral T cells.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ashton-Rickardt P. G., Bandeira A., Delaney J. R., Van Kaer L., Pircher H. P., Zinkernagel R. M., Tonegawa S. Evidence for a differential avidity model of T cell selection in the thymus. Cell. 1994 Feb 25;76(4):651–663. doi: 10.1016/0092-8674(94)90505-3. [DOI] [PubMed] [Google Scholar]
  2. Ballhausen W. G., Reske-Kunz A. B., Tourvieille B., Ohashi P. S., Parnes J. R., Mak T. W. Acquisition of an additional antigen specificity after mouse CD4 gene transfer into a T helper hybridoma. J Exp Med. 1988 Apr 1;167(4):1493–1498. doi: 10.1084/jem.167.4.1493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bertoletti A., Sette A., Chisari F. V., Penna A., Levrero M., De Carli M., Fiaccadori F., Ferrari C. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells. Nature. 1994 Jun 2;369(6479):407–410. doi: 10.1038/369407a0. [DOI] [PubMed] [Google Scholar]
  4. Bhardwaj V., Kumar V., Geysen H. M., Sercarz E. E. Degenerate recognition of a dissimilar antigenic peptide by myelin basic protein-reactive T cells. Implications for thymic education and autoimmunity. J Immunol. 1993 Nov 1;151(9):5000–5010. [PubMed] [Google Scholar]
  5. Bodmer H., Viville S., Benoist C., Mathis D. Diversity of endogenous epitopes bound to MHC class II molecules limited by invariant chain. Science. 1994 Mar 4;263(5151):1284–1286. doi: 10.1126/science.7510069. [DOI] [PubMed] [Google Scholar]
  6. Brooks A., Hartley S., Kjer-Nielsen L., Perera J., Goodnow C. C., Basten A., McCluskey J. Class II-restricted presentation of an endogenously derived immunodominant T-cell determinant of hen egg lysozyme. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3290–3294. doi: 10.1073/pnas.88.8.3290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Davenport M. P. Antagonists or altruists: do viral mutants modulate T-cell responses? Immunol Today. 1995 Sep;16(9):432–436. doi: 10.1016/0167-5699(95)80020-4. [DOI] [PubMed] [Google Scholar]
  8. De Magistris M. T., Alexander J., Coggeshall M., Altman A., Gaeta F. C., Grey H. M., Sette A. Antigen analog-major histocompatibility complexes act as antagonists of the T cell receptor. Cell. 1992 Feb 21;68(4):625–634. doi: 10.1016/0092-8674(92)90139-4. [DOI] [PubMed] [Google Scholar]
  9. Evavold B. D., Allen P. M. Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand. Science. 1991 May 31;252(5010):1308–1310. doi: 10.1126/science.1833816. [DOI] [PubMed] [Google Scholar]
  10. Evavold B. D., Sloan-Lancaster J., Allen P. M. Antagonism of superantigen-stimulated helper T-cell clones and hybridomas by altered peptide ligand. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2300–2304. doi: 10.1073/pnas.91.6.2300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Evavold B. D., Sloan-Lancaster J., Allen P. M. Tickling the TCR: selective T-cell functions stimulated by altered peptide ligands. Immunol Today. 1993 Dec;14(12):602–609. doi: 10.1016/0167-5699(93)90200-5. [DOI] [PubMed] [Google Scholar]
  12. Evavold B. D., Sloan-Lancaster J., Hsu B. L., Allen P. M. Separation of T helper 1 clone cytolysis from proliferation and lymphokine production using analog peptides. J Immunol. 1993 Apr 15;150(8 Pt 1):3131–3140. [PubMed] [Google Scholar]
  13. Evavold B. D., Sloan-Lancaster J., Wilson K. J., Rothbard J. B., Allen P. M. Specific T cell recognition of minimally homologous peptides: evidence for multiple endogenous ligands. Immunity. 1995 Jun;2(6):655–663. doi: 10.1016/1074-7613(95)90010-1. [DOI] [PubMed] [Google Scholar]
  14. Evavold B. D., Williams S. G., Hsu B. L., Buus S., Allen P. M. Complete dissection of the Hb(64-76) determinant using T helper 1, T helper 2 clones, and T cell hybridomas. J Immunol. 1992 Jan 15;148(2):347–353. [PubMed] [Google Scholar]
  15. Friedman A., Beller D. I. Simultaneous expression of Ia and cytocidal activity by macrophages, and the consequences for antigen presentation. Immunology. 1987 Aug;61(4):435–441. [PMC free article] [PubMed] [Google Scholar]
  16. Hagerty D. T., Allen P. M. Intramolecular mimicry. Identification and analysis of two cross-reactive T cell epitopes within a single protein. J Immunol. 1995 Sep 15;155(6):2993–3001. [PubMed] [Google Scholar]
  17. Haughton G., Arnold L. W., Bishop G. A., Mercolino T. J. The CH series of murine B cell lymphomas: neoplastic analogues of Ly-1+ normal B cells. Immunol Rev. 1986 Oct;93:35–51. doi: 10.1111/j.1600-065x.1986.tb01501.x. [DOI] [PubMed] [Google Scholar]
  18. Hedrick S. M., Matis L. A., Hecht T. T., Samelson L. E., Longo D. L., Heber-Katz E., Schwartz R. H. The fine specificity of antigen and Ia determinant recognition by T cell hybridoma clones specific for pigeon cytochrome c. Cell. 1982 Aug;30(1):141–152. doi: 10.1016/0092-8674(82)90020-4. [DOI] [PubMed] [Google Scholar]
  19. Hogquist K. A., Jameson S. C., Heath W. R., Howard J. L., Bevan M. J., Carbone F. R. T cell receptor antagonist peptides induce positive selection. Cell. 1994 Jan 14;76(1):17–27. doi: 10.1016/0092-8674(94)90169-4. [DOI] [PubMed] [Google Scholar]
  20. Hsu B. L., Evavold B. D., Allen P. M. Modulation of T cell development by an endogenous altered peptide ligand. J Exp Med. 1995 Feb 1;181(2):805–810. doi: 10.1084/jem.181.2.805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jameson S. C., Carbone F. R., Bevan M. J. Clone-specific T cell receptor antagonists of major histocompatibility complex class I-restricted cytotoxic T cells. J Exp Med. 1993 Jun 1;177(6):1541–1550. doi: 10.1084/jem.177.6.1541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jameson S. C., Hogquist K. A., Bevan M. J. Specificity and flexibility in thymic selection. Nature. 1994 Jun 30;369(6483):750–752. doi: 10.1038/369750a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Janeway C. A., Jr The T cell receptor as a multicomponent signalling machine: CD4/CD8 coreceptors and CD45 in T cell activation. Annu Rev Immunol. 1992;10:645–674. doi: 10.1146/annurev.iy.10.040192.003241. [DOI] [PubMed] [Google Scholar]
  24. Karin N., Mitchell D. J., Brocke S., Ling N., Steinman L. Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon gamma and tumor necrosis factor alpha production. J Exp Med. 1994 Dec 1;180(6):2227–2237. doi: 10.1084/jem.180.6.2227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Klenerman P., Rowland-Jones S., McAdam S., Edwards J., Daenke S., Lalloo D., Köppe B., Rosenberg W., Boyd D., Edwards A. Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature. 1994 Jun 2;369(6479):403–407. doi: 10.1038/369403a0. [DOI] [PubMed] [Google Scholar]
  26. Kuchroo V. K., Greer J. M., Kaul D., Ishioka G., Franco A., Sette A., Sobel R. A., Lees M. B. A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire. J Immunol. 1994 Oct 1;153(7):3326–3336. [PubMed] [Google Scholar]
  27. Lorenz R. G., Allen P. M. Direct evidence for functional self-protein/Ia-molecule complexes in vivo. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5220–5223. doi: 10.1073/pnas.85.14.5220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mannie M. D., Rosser J. M., White G. A. Autologous rat myelin basic protein is a partial agonist that is converted into a full antagonist upon blockade of CD4. Evidence for the integration of efficacious and nonefficacious signals during T cell antigen recognition. J Immunol. 1995 Mar 15;154(6):2642–2654. [PubMed] [Google Scholar]
  29. Marrack P., Ignatowicz L., Kappler J. W., Boymel J., Freed J. H. Comparison of peptides bound to spleen and thymus class II. J Exp Med. 1993 Dec 1;178(6):2173–2183. doi: 10.1084/jem.178.6.2173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Meier U. C., Klenerman P., Griffin P., James W., Köppe B., Larder B., McMichael A., Phillips R. Cytotoxic T lymphocyte lysis inhibited by viable HIV mutants. Science. 1995 Nov 24;270(5240):1360–1362. doi: 10.1126/science.270.5240.1360. [DOI] [PubMed] [Google Scholar]
  31. Miller A., Lider O., Roberts A. B., Sporn M. B., Weiner H. L. Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigen-specific triggering. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):421–425. doi: 10.1073/pnas.89.1.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nanda N. K., Arzoo K. K., Geysen H. M., Sette A., Sercarz E. E. Recognition of multiple peptide cores by a single T cell receptor. J Exp Med. 1995 Aug 1;182(2):531–539. doi: 10.1084/jem.182.2.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nicholson L. B., Greer J. M., Sobel R. A., Lees M. B., Kuchroo V. K. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity. 1995 Oct;3(4):397–405. doi: 10.1016/1074-7613(95)90169-8. [DOI] [PubMed] [Google Scholar]
  34. Perutz M. F. Structure and mechanism of haemoglobin. Br Med Bull. 1976 Sep;32(3):195–208. doi: 10.1093/oxfordjournals.bmb.a071363. [DOI] [PubMed] [Google Scholar]
  35. Pircher H., Rohrer U. H., Moskophidis D., Zinkernagel R. M., Hengartner H. Lower receptor avidity required for thymic clonal deletion than for effector T-cell function. Nature. 1991 Jun 6;351(6326):482–485. doi: 10.1038/351482a0. [DOI] [PubMed] [Google Scholar]
  36. Racioppi L., Ronchese F., Matis L. A., Germain R. N. Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligand-related differences in T cell receptor-dependent intracellular signaling. J Exp Med. 1993 Apr 1;177(4):1047–1060. doi: 10.1084/jem.177.4.1047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Racke M. K., Dhib-Jalbut S., Cannella B., Albert P. S., Raine C. S., McFarlin D. E. Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 1. J Immunol. 1991 May 1;146(9):3012–3017. [PubMed] [Google Scholar]
  38. Rudensky AYu, Preston-Hurlburt P., Hong S. C., Barlow A., Janeway C. A., Jr Sequence analysis of peptides bound to MHC class II molecules. Nature. 1991 Oct 17;353(6345):622–627. doi: 10.1038/353622a0. [DOI] [PubMed] [Google Scholar]
  39. Sebzda E., Wallace V. A., Mayer J., Yeung R. S., Mak T. W., Ohashi P. S. Positive and negative thymocyte selection induced by different concentrations of a single peptide. Science. 1994 Mar 18;263(5153):1615–1618. doi: 10.1126/science.8128249. [DOI] [PubMed] [Google Scholar]
  40. Sloan-Lancaster J., Evavold B. D., Allen P. M. Induction of T-cell anergy by altered T-cell-receptor ligand on live antigen-presenting cells. Nature. 1993 May 13;363(6425):156–159. doi: 10.1038/363156a0. [DOI] [PubMed] [Google Scholar]
  41. Spain L. M., Jorgensen J. L., Davis M. M., Berg L. J. A peptide antigen antagonist prevents the differentiation of T cell receptor transgenic thymocytes. J Immunol. 1994 Feb 15;152(4):1709–1717. [PubMed] [Google Scholar]
  42. Sprent J. T and B memory cells. Cell. 1994 Jan 28;76(2):315–322. doi: 10.1016/0092-8674(94)90338-7. [DOI] [PubMed] [Google Scholar]
  43. Stockinger B., Grant C. F., Hausmann B. Localization of self antigen: implications for antigen presentation and induction of tolerance. Eur J Immunol. 1993 Jan;23(1):6–11. doi: 10.1002/eji.1830230103. [DOI] [PubMed] [Google Scholar]
  44. Turner J. M., Brodsky M. H., Irving B. A., Levin S. D., Perlmutter R. M., Littman D. R. Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell. 1990 Mar 9;60(5):755–765. doi: 10.1016/0092-8674(90)90090-2. [DOI] [PubMed] [Google Scholar]
  45. Urban R. G., Chicz R. M., Vignali D. A., Strominger J. L. The dichotomy of peptide presentation by class I and class II MHC proteins. Chem Immunol. 1993;57:197–234. [PubMed] [Google Scholar]
  46. Vasquez N. J., Kane L. P., Hedrick S. M. Intracellular signals that mediate thymic negative selection. Immunity. 1994 Apr;1(1):45–56. doi: 10.1016/1074-7613(94)90008-6. [DOI] [PubMed] [Google Scholar]
  47. Vignali D. A., Moreno J., Schiller D., Hämmerling G. J. Does CD4 help to maintain the fidelity of T cell receptor specificity? Int Immunol. 1992 May;4(5):621–626. doi: 10.1093/intimm/4.5.621. [DOI] [PubMed] [Google Scholar]
  48. Viner N. J., Nelson C. A., Unanue E. R. Identification of a major I-Ek-restricted determinant of hen egg lysozyme: limitations of lymph node proliferation studies in defining immunodominance and crypticity. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2214–2218. doi: 10.1073/pnas.92.6.2214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Windhagen A., Scholz C., Höllsberg P., Fukaura H., Sette A., Hafler D. A. Modulation of cytokine patterns of human autoreactive T cell clones by a single amino acid substitution of their peptide ligand. Immunity. 1995 Apr;2(4):373–380. doi: 10.1016/1074-7613(95)90145-0. [DOI] [PubMed] [Google Scholar]
  50. Wucherpfennig K. W., Strominger J. L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell. 1995 Mar 10;80(5):695–705. doi: 10.1016/0092-8674(95)90348-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Yule T. D., Basten A., Allen P. M. Hen egg-white lysozyme-specific T cells elicited in hen egg-white lysozyme-transgenic mice retain an imprint of self-tolerance. J Immunol. 1993 Sep 15;151(6):3057–3069. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES