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. 1983 May 1;157(5):1618–1634. doi: 10.1084/jem.157.5.1618

Inhibition of antigen-specific T lymphocyte activation by structurally related Ir gene-controlled polymers. Evidence of specific competition for accessory cell antigen presentation

PMCID: PMC2186997  PMID: 6189942

Abstract

The interaction of nominal Ag with major histocompatibility complex (MHC)-restricted T cells and accessory cells was studied by analyzing the effect of structurally related antigens on the response of antigen- specific MHC-restricted T cell hybridomas. The copolymer L-glutamic acid50-L-tyrosine50 (GT) completely inhibits the response of L-glutamic acid60-L-alanine40-L-tyrosine10 (GAT)-specific, I-Ad-restricted T cell hybridomas to GAT plus accessory cells. This inhibition is specific, as hybridomas of other specificities are not inhibited under identical conditions, and is unique to the GT antigen, as other similar copolymers are not inhibitory. The inhibitory effect is reversible by adding increasing amounts of GAT. Antigen-pulsing experiments localized the inhibition to the level of antigen-presenting cell (APC). GT- prepulsed APC are not inhibitory in cell-mixing experiments and can present other antigens. GT only inhibits the nominal antigen-directed component of a GAT-specific, autoreactive hybrid's response. Together these findings suggest that GT causes inhibition by competing for GAT association at the accessory cell. GT interferes with GAT presentation by an I-Adxb F1 APC to a BALB/c, I-Ad-restricted, but not B10, I-Ab- restricted, T cell hybridoma, and GT inhibits presentation by GAT- prepulsed APC. The implications of these findings for MHC-restricted presentation of antigen are discussed.

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Selected References

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  1. Benacerraf B. A hypothesis to relate the specificity of T lymphocytes and the activity of I region-specific Ir genes in macrophages and B lymphocytes. J Immunol. 1978 Jun;120(6):1809–1812. [PubMed] [Google Scholar]
  2. Benacerraf B., Germain R. N. The immune response genes of the major histocompatibility complex. Immunol Rev. 1978;38:70–119. doi: 10.1111/j.1600-065x.1978.tb00385.x. [DOI] [PubMed] [Google Scholar]
  3. Bevan M. J. In a radiation chimaera, host H-2 antigens determine immune responsiveness of donor cytotoxic cells. Nature. 1977 Sep 29;269(5627):417–418. doi: 10.1038/269417a0. [DOI] [PubMed] [Google Scholar]
  4. Chesnut R. W., Colon S. M., Grey H. M. Antigen presentation by normal B cells, B cell tumors, and macrophages: functional and biochemical comparison. J Immunol. 1982 Apr;128(4):1764–1768. [PubMed] [Google Scholar]
  5. Cohn M., Epstein R. T-cell inhibition of humoral responsiveness. II. Theory on the role of restrictive recognition in immune regulation. Cell Immunol. 1978 Aug;39(1):125–153. doi: 10.1016/0008-8749(78)90089-8. [DOI] [PubMed] [Google Scholar]
  6. Debré P., Kapp J. A., Benacerraf B. Genetic control of specific immune suppression. I. Experimental conditions for the stimulation of suppressor cells by the copolymer L-glutamic acid50-L-tyrosine50 (GT) in nonresponder BALB/c mice. J Exp Med. 1975 Dec 1;142(6):1436–1446. doi: 10.1084/jem.142.6.1436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Debré P., Waltenbaugh C., Dorf M. E., Benacerraf B. Genetic control of specific immune suppression. IV. Responsiveness to the random copolymer L-glutamic acid50-L-tyrosine50 induced in BALB/c mice by cyclophosphamide. J Exp Med. 1976 Jul 1;144(1):277–281. doi: 10.1084/jem.144.1.277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dorf M. E., Benacerraf B. Complementation of H-2-linked Ir genes in the mouse. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3671–3675. doi: 10.1073/pnas.72.9.3671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Germain R. N. Accessory cell stimulation of T cell proliferation requires active antigen processing, Ia-restricted antigen presentation, and a separate nonspecific 2nd signal. J Immunol. 1981 Nov;127(5):1964–1966. [PubMed] [Google Scholar]
  10. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  11. Glimcher L. H., Kim K. J., Green I., Paul W. E. Ia antigen-bearing B cell tumor lines can present protein antigen and alloantigen in a major histocompatibility complex-restricted fashion to antigen-reactive T cells. J Exp Med. 1982 Feb 1;155(2):445–459. doi: 10.1084/jem.155.2.445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Green I., Paul W. E., Benacerraf B. Genetic control of immunological responsiveness in guinea pigs to 2,4-dinitrophenyl conjugates of poly-L-arginine, protamine, and poly-L-ornithine. Proc Natl Acad Sci U S A. 1969 Nov;64(3):1095–1102. doi: 10.1073/pnas.64.3.1095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Heber-Katz E., Schwartz R. H., Matis L. A., Hannum C., Fairwell T., Appella E., Hansburg D. Contribution of antigen-presenting cell major histocompatibility complex gene products to the specificity of antigen-induced T cell activation. J Exp Med. 1982 Apr 1;155(4):1086–1099. doi: 10.1084/jem.155.4.1086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Janeway C. A., Wigzell H., Binz H. Two different VH gene products make up the T-cell receptors. Scand J Immunol. 1976;5(9):993–1001. doi: 10.1111/j.1365-3083.1976.tb03051.x. [DOI] [PubMed] [Google Scholar]
  15. Jones P. P., Murphy D. B., McDevitt H. O. Two-gene control of the expression of a murine Ia antigen. J Exp Med. 1978 Oct 1;148(4):925–939. doi: 10.1084/jem.148.4.925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kappler J. W., Marrack P. The role of H-2 linked genes in helper T-cell function. IV. Importance of T-cell genotype and host environment in I-region and Ir gene expression. J Exp Med. 1978 Dec 1;148(6):1510–1522. doi: 10.1084/jem.148.6.1510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kappler J. W., Skidmore B., White J., Marrack P. Antigen-inducible, H-2-restricted, interleukin-2-producing T cell hybridomas. Lack of independent antigen and H-2 recognition. J Exp Med. 1981 May 1;153(5):1198–1214. doi: 10.1084/jem.153.5.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Katz D. H., Benacerraf B. The function and interrelationships of T-cell receptors, Ir genes and other histocompatibility gene products. Transplant Rev. 1975;22:175–195. doi: 10.1111/j.1600-065x.1975.tb01559.x. [DOI] [PubMed] [Google Scholar]
  19. Kim K. J., Kanellopoulos-Langevin C., Merwin R. M., Sachs D. H., Asofsky R. Establishment and characterization of BALB/c lymphoma lines with B cell properties. J Immunol. 1979 Feb;122(2):549–554. [PubMed] [Google Scholar]
  20. LEVINE B. B., BENACERRAF B. GENETIC CONTROL IN GUINEA PIGS OF IMMUNE RESPONSE TO CONJUGATES OF HAPTENS AND POLY-L-LYSINE. Science. 1965 Jan 29;147(3657):517–518. doi: 10.1126/science.147.3657.517. [DOI] [PubMed] [Google Scholar]
  21. Langman R. E. Cell-mediated immunity and the major histocompatibility complex. Rev Physiol Biochem Pharmacol. 1978;81:1–37. doi: 10.1007/BFb0034090. [DOI] [PubMed] [Google Scholar]
  22. Lerner E. A., Matis L. A., Janeway C. A., Jr, Jones P. P., Schwartz R. H., Murphy D. B. Monoclonal antibody against an Ir gene product? J Exp Med. 1980 Oct 1;152(4):1085–1101. doi: 10.1084/jem.152.4.1085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Marshak-Rothstein A., Fink P., Gridley T., Raulet D. H., Bevan M. J., Gefter M. L. Properties and applications of monoclonal antibodies directed against determinants of the Thy-1 locus. J Immunol. 1979 Jun;122(6):2491–2497. [PubMed] [Google Scholar]
  24. Matis L. A., Jones P. P., Murphy D. B., Hedrick S. M., Lerner E. A., Janeway C. A., Jr, McNicholas J. M., Schwartz R. H. Immune response gene function correlates with the expression of an Ia antigen. II. A quantitative deficiency in Ae:E alpha complex expression causes a corresponding defect in antigen-presenting cell function. J Exp Med. 1982 Feb 1;155(2):508–523. doi: 10.1084/jem.155.2.508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Matzinger P. A one-receptor view of T-cell behaviour. Nature. 1981 Aug 6;292(5823):497–501. doi: 10.1038/292497a0. [DOI] [PubMed] [Google Scholar]
  26. McDevitt H. O., Chinitz A. Genetic control of the antibody response: relationship between immune response and histocompatibility (H-2) type. Science. 1969 Mar 14;163(3872):1207–1208. doi: 10.1126/science.163.3872.1207. [DOI] [PubMed] [Google Scholar]
  27. Michaelides M., Sandrin M., Morgan G., McKenzie I. F., Ashman R., Melvold R. W. Ir gene function in an I-A subregion mutant B6.C-H-2bm12. J Exp Med. 1981 Feb 1;153(2):464–469. doi: 10.1084/jem.153.2.464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Oi V. T., Jones P. P., Goding J. W., Herzenberg L. A., Herzenberg L. A. Properties of monoclonal antibodies to mouse Ig allotypes, H-2, and Ia antigens. Curr Top Microbiol Immunol. 1978;81:115–120. doi: 10.1007/978-3-642-67448-8_18. [DOI] [PubMed] [Google Scholar]
  29. Rock K. L., Benacerraf B. The role of Ia molecules in the activation of T lymphocytes. III. Antigen-specific, Ia-restricted, interleukin 2-producing T cell hybridomas with detectable affinity for the restricting I-A molecule. J Exp Med. 1983 Jan 1;157(1):359–364. doi: 10.1084/jem.157.1.359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rock K. L. The role of Ia molecules in the activation of T lymphocytes. I. The activation of an IL 1-dependent IL 2-producing T cell hybridoma by Con A requires an interaction, which is not H-2-restricted, with an Ia-bearing accessory cell. J Immunol. 1982 Oct;129(4):1360–1366. [PubMed] [Google Scholar]
  31. Rosenthal A. S. Determinant selection and macrophage function in genetic control of the immune response. Immunol Rev. 1978;40:136–152. doi: 10.1111/j.1600-065x.1978.tb00404.x. [DOI] [PubMed] [Google Scholar]
  32. Rosenthal A. S., Shevach E. M. Function of macrophages in antigen recognition by guinea pig T lymphocytes. I. Requirement for histocompatible macrophages and lymphocytes. J Exp Med. 1973 Nov 1;138(5):1194–1212. doi: 10.1084/jem.138.5.1194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rosenwasser L. J., Barcinski M. A., Schwartz R. H., Rosenthal A. S. Immune response gene control of determinant selection. II. Genetic control of the murine T lymphocyte proliferative response to insulin. J Immunol. 1979 Jul;123(1):471–476. [PubMed] [Google Scholar]
  34. Schwartz R. H., Yano A., Paul W. E. Interaction between antigen-presenting cells and primed T lymphocytes: an assessment of Ir gene expression in the antigen-presenting cell. Immunol Rev. 1978;40:153–180. doi: 10.1111/j.1600-065x.1978.tb00405.x. [DOI] [PubMed] [Google Scholar]
  35. Shevach E. M., Rosenthal A. S. Function of macrophages in antigen recognition by guinea pig T lymphocytes. II. Role of the macrophage in the regulation of genetic control of the immune response. J Exp Med. 1973 Nov 1;138(5):1213–1229. doi: 10.1084/jem.138.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sy M. S., Lee S. H., Tsurufuji M., Rock K. L., Benacerraf B., Finberg R. Two distinct mechanisms regulate the in vivo generation of cytotoxic T cells. J Exp Med. 1982 Sep 1;156(3):918–923. doi: 10.1084/jem.156.3.918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Thomas D. W., Meltz S. K., Wilner G. D. Nature of T lymphocyte recognition of macrophage-associated antigens. II. Macrophage determination of guinea pig T cell responses to human fibrinopeptide B. J Immunol. 1979 Sep;123(3):1299–1302. [PubMed] [Google Scholar]
  38. Werdelin O. Chemically related antigens compete for presentation by accessory cells to T cells. J Immunol. 1982 Nov;129(5):1883–1891. [PubMed] [Google Scholar]
  39. White J., Haskins K. M., Marrack P., Kappler J. Use of I region-restricted, antigen-specific T cell hybridomas to produce idiotypically specific anti-receptor antibodies. J Immunol. 1983 Mar;130(3):1033–1037. [PubMed] [Google Scholar]
  40. Ziegler H. K., Unanue E. R. Decrease in macrophage antigen catabolism caused by ammonia and chloroquine is associated with inhibition of antigen presentation to T cells. Proc Natl Acad Sci U S A. 1982 Jan;79(1):175–178. doi: 10.1073/pnas.79.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zinkernagel R. M., Callahan G. N., Althage A., Cooper S., Klein P. A., Klein J. On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition? J Exp Med. 1978 Mar 1;147(3):882–896. doi: 10.1084/jem.147.3.882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. von Boehmer H., Haas W., Jerne N. K. Major histocompatibility complex-linked immune-responsiveness is acquired by lymphocytes of low-responder mice differentiating in thymus of high-responder mice. Proc Natl Acad Sci U S A. 1978 May;75(5):2439–2442. doi: 10.1073/pnas.75.5.2439. [DOI] [PMC free article] [PubMed] [Google Scholar]

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