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Induction of Peripheral Tolerance in Dual TCR T Cells: an Evidence for Non-dominant Signaling by One TCR

  • Hah, Chae-Rim (Division of Molecular Life Sciences and College of Pharmacy, Ewha Womans University) ;
  • Kim, Mi-Hyung (Division of Molecular Life Sciences and College of Pharmacy, Ewha Womans University) ;
  • Kim, Kil-Hyoun (Division of Molecular Life Sciences and College of Pharmacy, Ewha Womans University)
  • Published : 2005.05.31

Abstract

Recently, the existence of T cells with dual T cell receptor (TCR) in the immune system is generally accepted, while it has been controversial whether signals through one TCR would affect the functions of the other. In this study T cells expressing two different TCR were obtained from cross-hybrids of LCMV and AND TCR transgenic mice specific for the gp33 and peptide fragment of PCC (fPCC), respectively. Peptide stimulation demonstrated that the dual TCR T cells functioned independently in an antigen-specific manner. To examine whether the tolerance targeted for the one TCR affects the responsiveness of the other, the cross-hybrids were treated with gp33. Although T cells from F1 mice were rendered anergenic to gp33, no functional changes to fPCC were observed in terms of cellular proliferation and IL-2 secretion, suggesting that the dual TCR T cells remained reactive to fPCC. We therefore propose that signaling through the TCR is receptor-specific and 'negative dominance' of one TCR by tolerance induction is not applicable in this dual TCR system.

Keywords

References

  1. Aichele, P., Brduscha-Reim, K., Oehen, S., Odermatt, B., Zinkernagel, R. M., Hengartner, H. and Pircher, H. (1995) Brief definitive report: T cell priming versus T cell tolerance induced by synthetic peptides. J. Exp. Med. 182, 261-266 https://doi.org/10.1084/jem.182.1.261
  2. Aichele, P., Brduscha-Reim, K., Oehen, S., Odermatt, B., Zinkernagel, R. M., Hengartner, H. and Pircher, H. (1997) Peptide antigen treatment of naïve and virus-immune mice: antigen-specific tolerance versus immunopathology. Immunity 6, 519-529 https://doi.org/10.1016/S1074-7613(00)80340-4
  3. Blichfeldt, E., Munthe, L. A., Rotnes, J. S. and Bogen, B. (1996) Dual T cell receptor T cells have a decreased sensitivity to physiological ligands due to reduced density of each T cell receptor. Eur. J. Immunol. 26, 2876-2884 https://doi.org/10.1002/eji.1830261211
  4. von Boehmer, H. (1993) Developmental biology of T cells in T cell receptor transgenic mice. Ann. Rev. Immunol. 8, 531-556 https://doi.org/10.1146/annurev.immunol.8.1.531
  5. von Boehmer, H. and Kisielow, P. (1998) Self-nonself discrimination by T cells. Science 248, 1369-1373 https://doi.org/10.1126/science.1972594
  6. Borgulya, P., Kishi, H., Uematsu, Y. and von Boehmer, H. (1992) Exclusion and inclusion of and T cell receptor alleles. Cell 69, 529-537 https://doi.org/10.1016/0092-8674(92)90453-J
  7. Burkly, L. C., Lo, D., Kangawa, O., Brinster, R. L. and Flavall, R. A. (1989) T-cell tolerance by clonal anergy in transgenic mice with nonlymphoid expression of MHC II I-E. Nature 342, 564- 566 https://doi.org/10.1038/342564a0
  8. Casanova, I. L., Romero, P., Widmann, C., Kourilsky, P. and Maryanski, J. L. (1991) T cell receptor genes in a series of class I major histocompatibility complex-restricted cytotoxic T lymphocyte clones specific for a Plasmodium berghei nonapeptide: implication for T cell allelic exclusion and antigen-specific repertoire. J. Exp. Med. 174, 1371-1383 https://doi.org/10.1084/jem.174.6.1371
  9. Daniels, M. A., Schober, S. L., Hogquist, K. A. and Jameson, S. C. (1999) Cutting edge: a test of the dominant negative signal model for TCR antagonism. J. Immunol. 163, 1750-1754
  10. Dittel, B. N., Stefanova, I. and Germaim, R. N. (1999) Crossantagonism of a T cell clone expressing two distinct T cell receptors. Immunity 11, 289-298 https://doi.org/10.1016/S1074-7613(00)80104-1
  11. Ferber, I., Schonrich, G., Schenkel, J., Mellor, A. L., Hammerling, G. J. and Arnold, B. (1994) Levels of peripheral T-cell tolerance induced by different doses of tolerogen. Science 263, 674-676 https://doi.org/10.1126/science.8303275
  12. Fossati, G., Cooke, A., Papafio, R. Q., Haskins, K. and Stokinger, B. (1999) Triggering a second T cell receptor on diabetogenic T cells can prevent induction of diabetes. J. Exp. Med. 190, 577-583 https://doi.org/10.1084/jem.190.4.577
  13. George, Y. L., Fairchild, P. J., Smith, R. M., Prowle, J. R., Kioussis, D. and Wraith, D. C. (1995) Low avidity recognition of self-antigen by T cells permits escape from central tolerance. Immunity 3, 407-415 https://doi.org/10.1016/1074-7613(95)90170-1
  14. Hammering, G. J., Schonrich, G., Ferber, I. and Arnold, B. (1993) Peripheral tolerance as a multistep mechanism. Immunol. Rev. 133, 93-104 https://doi.org/10.1111/j.1600-065X.1993.tb01511.x
  15. Heath, W. R. and Miller, J. F. A. P. (1993) Expression of two alpha chains on the surface of T cells in T cell receptor transgenic mice. J. Exp. Med. 178, 1807-1811 https://doi.org/10.1084/jem.178.5.1807
  16. Heath, W. R., Carbone, F. R., Bertolino, P., Kelly, J., Cose, S. and Miller, J. F. A. P. (1995) Expression of two T cell receptor a chains on the surface of normal murine T cells. Eur. J. Immunol. 25, 1617-1623 https://doi.org/10.1002/eji.1830250622
  17. Janeway, C. A. (1992) The T cell receptor as a multicomponent signaling machine: CD4/CD8 coreceptors and CD45 in T cell activation. Annu. Rev. Immunol. 10, 645-674 https://doi.org/10.1146/annurev.iy.10.040192.003241
  18. Kappler, J. W., Roehm, N. and Marrack, P. (1987) T cell tolerance by clonal elimination in the thymus. Cell 49, 273-280 https://doi.org/10.1016/0092-8674(87)90568-X
  19. Kappler, J. W., Staerz, U. D., White, J. and Marrack, P. (1988) Self tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex. Nature 332, 35-40 https://doi.org/10.1038/332035a0
  20. Kaye, J., Hsu, M., Sauron, M., Jameson, S. C., Gascoigne, N. R. J. and Hedrick, S. M. (1989) Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor. Nature 341, 746-749 https://doi.org/10.1038/341746a0
  21. Kyburz, D., Aichele, P., Speiser, D. E., Hengartner, H., Zinkernagel, R. M. and Pircher, H. (1993) T cell immunity after a viral infection versus T cell tolerance induced by soluble viral peptide. Eur. J. Immunol. 23, 1956-1962 https://doi.org/10.1002/eji.1830230834
  22. MacDonald, H. R., Schineider, R., Lees, R. K., Howe, R. C., Acha-Orbea, H., Festenstein, H., Zinkernagel, R. M. and Hengartner, H. (1988) T cell receptor V$\beta$ use predicts reactivity and tolerance to Misa-encoded antigens. Nature 332, 40-45 https://doi.org/10.1038/332040a0
  23. Miller, J. F. A. P. and Morahan, G. (1992) Peripheral T Cell Tolerance. Annu. Rev. Immunol. 10, 51-69 https://doi.org/10.1146/annurev.iy.10.040192.000411
  24. Moscophidis, D., Lechner, F., Pircher, H. P. and Zinkernagel, R. M. (1993) Virus persistence in acutely infected immunocompetent mice by exhausting of antiviral cytotoxic effector T cells. Nature 362, 758-761 https://doi.org/10.1038/362758a0
  25. Ohashi, P. S., Oehen, S., Buerki, K., Pirdher, H., Ohashi, C. T., Odermatt, B., Malissen, B., Zinkernagel, R. M. and Hengartner, H. (1991) Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65, 305- 317 https://doi.org/10.1016/0092-8674(91)90164-T
  26. Oldstone, M. B. (1987) Molecular mimicry and autoimmune disease. Cell 50, 819-820 https://doi.org/10.1016/0092-8674(87)90507-1
  27. Padovan, E., Casorati, G., Dellabona, P., Meyer, S., Brockhaus, M. and Lanzavecchia, A. (1993) Expression of two T cell receptor a chains: dual receptor T cells. Science 262, 422-424 https://doi.org/10.1126/science.8211163
  28. Pircher, H., Burki, K., Lang, R., Hengartner, H. and Zinkernagel, R. M. (1989) Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature 342, 559- 561 https://doi.org/10.1038/342559a0
  29. Racioppi, L., Matarese, G., Doro, U., Pascale, M., Masci, A. M., Fontana, S. and Zappacosta, S. (1996) The role of CD4-Lck in T-cell receptor antagonism: evidence for negative signaling. Proc. Natl. Acad. Sci. USA 93, 10360-10365
  30. Rammensee, H. G., Krosschewski, R. and Frangoulis, B. (1989) Clonal anergy induced in mature $V\beta6^{+}$ T lymphocytes on immunizing Mis-1 mice with Mis-1 expression cells. Nature 339, 541-544 https://doi.org/10.1038/339541a0
  31. Robertson, J. M. and Evavold, B. D. (1999) Cutting edge: dueling TCRs: peptide antagonism of $CD4^{+}$ T cells with dual antigen specificities. J. Immunol. 63, 1750-1754
  32. Rocha, B. and von Boehmer, H. (1991) Peripheral selection of the T cell repertoire. Science 251, 1225-1228 https://doi.org/10.1126/science.1900951
  33. Rocken, M., Urban, J. F. and Shevach, E. M. (1992) Infection breaks T-cell tolerance. Nature 359, 79-82 https://doi.org/10.1038/359079a0
  34. Sarukhan, A., Garcia, C., Lanoue, A. and von Boehmer, H. (1998) Allelic inclusion of T cell receptor $\alpha$genes poses an autoimmune hazard due to low-level expression of autospecific receptors. Immunity 8, 563-570 https://doi.org/10.1016/S1074-7613(00)80561-0
  35. Schild, H. J., Rotzschje, O., Kalbacher, H. and Rammensee, H. G. (1990) Limit of T cell tolerance to self-proteins by peptide presentation. Science 247, 1587-1589 https://doi.org/10.1126/science.2321019
  36. Sha, W. C., Nelson, C. A., Newberry, R. D., Kranz, D. M., Russell, J. H. and Loh, D. Y. (1988) Positive and negative selection of an antigen receptor on T cells transgenic mice. Nature 1336, 73-76 https://doi.org/10.1038/336073a0
  37. Stotz, S. H., Bolliger, L., Carbone, F. R. and Palmer, E. (1999) T cell receptor (TCR) antagonism without a negative signal: evidence from T cell hybridomas expressing two independent TCRs. J. Exp. Med. 189, 253-263 https://doi.org/10.1084/jem.189.2.253
  38. Webb, S., Morris, C. and Sprent, J. (1990) Extrathymic tolerance of mature cells: clonal elimination as a consequence of immunity. Cell 63, 1249-56 https://doi.org/10.1016/0092-8674(90)90420-J
  39. Zal, T., Weiss, S., Mellor, A. and Stockinger, B. (1996) Expression of a second receptor rescues self-specific T cells from thymic deletion and allows activation of autoreactive effector function. Proc. Natl. Acad. Sci. USA 93, 9102-9107
  40. Zal, T., Zal, M. A. and Gascoigne, N. R. J. (2002) Inhibition of T cell receptor-coreceptor interactions by antagonist ligands visualized by live FRET imaging of the T-hybridoma immunological synapse. Immunity 16, 521-534 https://doi.org/10.1016/S1074-7613(02)00301-1

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