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. 1979 Jan 1;149(1):40–57. doi: 10.1084/jem.149.1.40

Gene complementation in the T-lymphocyte proliferative response to poly (Glu55Lys36Phe9)n. A demonstration that both immune response gene products must be expressed in the same antigen-presenting cell

PMCID: PMC2184747  PMID: 105077

Abstract

The immune response (Ir) to the random copolymer GLphi depends upon the function of two Ir genes, Ir-GLphi-beta[beta] and Ir-GLphi- alpha[alpha], mapped to the I-A and I-E/C subregions of the major histocompatibility complex, respectively. In this paper, the site(s) of expression of the products of these two Ir genes was examined by evaluating T-lymphocyte proliferative responses of bone marrow radiation chimeras. Chimeras were created in [alpha+beta- X alpha- beta+]F1 responder mice by lethal irradiation and reconstitution with a mixture of bone marrow cells from both parental strains. These chimeras failed to respond to GLphi, although they were capable or responding to the much weaker antigens, (T,G)-A--L, TEPC-15, pigeon cytochrome c, and (H,G)-A--L. This failure to respond to GLphi was shown not to be the result of a cryptic mixed lymphocyte reaction, as similar chimeras created in (alpha+beta+ X alpha-beta+)F1 mice responded well to GLphi, although they possessed almost the same potential histoincompatibility. Furthermore, the lack of response to GLphi could not be attributed to a general failure of the two parental cell types in the chimeras to collaboratc with each other, as each chimeric parental cell type could respond to dinitrophenyl conjugated ovalbumin presented on nonimmune spleen cells from the other parent. Thus, the failure of low responder parental into F1 high responder chimeras to generate an immune response to GLphi suggests that immune competence for this antigen requires at least one cell type in the immune system to express gene products of both the Ir-glphi-alpha and -beta genes, i.e. one cell must be of high responder genotype. The the antigen-presenting cell is one such cell type was shown by experiments in which GLphi-primed T lymphocytes from responder F1 mice were stimulated with antigen bound to nonimmune spleen cells. Only spleen cells from responder F1 and recombinant mice could present GLphi. Neither of the two complementing nonresponder parental spleen cell populations, either alone or mixed together, could present GLphi, although both could present purified protein derivative of tuberculin. This was shown to be the case for T cells positively selected in vitro as well as freshly explanted T cells. Thus, both Ir- GLphi-alpha and Ir-GLphi-beta gene products must be expressed in the same antigen-presenting cell to generate a T-lymphocyte proliferative response to GLphi. The implications of these findings for models of two gene complementation are discussed.

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Selected References

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  1. 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]
  2. Boehmer H., Sprent J., Nabholz M. Tolerance to histocompatibility determinants in tetraparental bone marrow chimeras. J Exp Med. 1975 Feb 1;141(2):322–334. doi: 10.1084/jem.141.2.322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chesebro B., Metzger H. Affinity labeling of a phosphorylcholine binding mouse myeloma protein. Biochemistry. 1972 Feb 29;11(5):766–771. doi: 10.1021/bi00755a014. [DOI] [PubMed] [Google Scholar]
  4. Corradin G., Etlinger H. M., Chiller J. M. Lymphocyte specificity to protein antigens. I. Characterization of the antigen-induced in vitro T cell-dependent proliferative response with lymph node cells from primed mice. J Immunol. 1977 Sep;119(3):1048–1053. [PubMed] [Google Scholar]
  5. David C. S., Shreffler D. C., Frelinger J. A. New lymphocyte antigen system (Lna) controlled by the Ir region of the mouse H-2 complex. Proc Natl Acad Sci U S A. 1973 Sep;70(9):2509–2514. doi: 10.1073/pnas.70.9.2509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Fathman C. G., Nabholz M. In vitro secondary mixed leukocyte reaction (MLR). II. Interaction MLR determinants expressed by F1 cells. Eur J Immunol. 1977 Jun;7(6):370–374. doi: 10.1002/eji.1830070609. [DOI] [PubMed] [Google Scholar]
  8. Gorczynski R. M., MacRae S. Differentiation of functionally active mouse T-lymphocytes from functionally inactive bone marrow precursors. Immunology. 1977 Nov;33(5):697–712. [PMC free article] [PubMed] [Google Scholar]
  9. Günther E., Rüde E. Genetic complementation of histocompatibility-linked Ir genes in the rat. J Immunol. 1975 Nov;115(5):1387–1393. [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. KATCHALSKI E., SELA M. Synthesis and chemical properties of poly-alpha-amino acids. Adv Protein Chem. 1958;13:243–492. doi: 10.1016/s0065-3233(08)60600-2. [DOI] [PubMed] [Google Scholar]
  13. Keck K. Ir gene control of carrier recognition. III. Cooperative recognition of two or more carrier determinants on insulins of different species. Eur J Immunol. 1977 Nov;7(11):811–816. doi: 10.1002/eji.1830071113. [DOI] [PubMed] [Google Scholar]
  14. Meo T., Vives J., Miggiano V., Shreffler D. A major role for the Ir-1 region of the mouse H-2 complex in the mixed leukocyte reaction. Transplant Proc. 1973 Mar;5(1):377–381. [PubMed] [Google Scholar]
  15. Miller J. F., Vadas M. A., Whitelaw A., Gamble J. Role of major histocompatibility complex gene products in delayed-type hypersensitivity. Proc Natl Acad Sci U S A. 1976 Jul;73(7):2486–2490. doi: 10.1073/pnas.73.7.2486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Munro A. J., Taussig M. J. Two genes in the major histocompatibility complex control immune response. Nature. 1975 Jul 10;256(5513):103–106. doi: 10.1038/256103a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Okuda K., David C. S., Shreffler D. C. The role of gene products of the I-J subregion in mixed lymphocyte reactions. J Exp Med. 1977 Dec 1;146(6):1561–1573. doi: 10.1084/jem.146.6.1561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Paul W. E., Benacerraf B. Functional specificity of thymus- dependent lymphocytes. Science. 1977 Mar 25;195(4284):1293–1300. doi: 10.1126/science.320663. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Rosenwasser L. J., Rosenthal A. S. Adherent cell function in murine T lymphocyte antigen recognition. I. A. macrophage-dependent T cell proliferation assay in the mouse. J Immunol. 1978 Jun;120(6):1991–1995. [PubMed] [Google Scholar]
  21. SELA M., FUCHS S., ARNON R. Studies on the chemical basis of the antigenicity of proteins. 5. Synthesis, characterization and immunogenicity of some multichain and linear polypeptides containing tyrosine. Biochem J. 1962 Oct;85:223–235. doi: 10.1042/bj0850223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Sachs D. H., Winn H. J., Russell P. S. The immunologic response to xenografts. Recognition of mouse H-2 histocompatibility antigens by the rat. J Immunol. 1971 Aug;107(2):481–492. [PubMed] [Google Scholar]
  23. Schwartz R. H. A clonal deletion model for Ir gene control of the immune response. Scand J Immunol. 1978;7(1):3–10. doi: 10.1111/j.1365-3083.1978.tb00420.x. [DOI] [PubMed] [Google Scholar]
  24. Schwartz R. H., Berzofsky J. A., Horton C. L., Schechter A. N., Sachs D. H. Genetic control of the T lymphocyte proliferative response to staphylococcal nuclease: evidence for multiple MHC-linked Ir gene control. J Immunol. 1978 May;120(5):1741–1749. [PubMed] [Google Scholar]
  25. Schwartz R. H., David C. S., Dorf M. E., Benacerraf B., Paul W. E. Inhibition of dual Ir gene-controlled T-lymphocyte proliferative response to poly (Glu56Lys35Phe9)n with anti-Ia antisera directed against products of either I-A or I-C subregion. Proc Natl Acad Sci U S A. 1978 May;75(5):2387–2391. doi: 10.1073/pnas.75.5.2387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schwartz R. H., Dorf M. E., Benacerraf B., Paul W. E. The requirement for two complementing Ir-GLphi immune response genes in the T-lymphocyte proliferative response to poly-(Glu53Lys36Phe11). J Exp Med. 1976 Apr 1;143(4):897–905. doi: 10.1084/jem.143.4.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schwartz R. H., Horton C. L., Paul W. E. T-lymphocyte-enriched murine peritoneal exudate cells. IV. Genetic control of cross-stimulation at the T-cell level. J Exp Med. 1977 Feb 1;145(2):327–343. doi: 10.1084/jem.145.2.327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schwartz R. H., Jackson L., Paul W. E. T lymphocyte-enriched murine peritoneal exudate cells. I. A reliable assay for antigen-induced T lymphocyte proliferation. J Immunol. 1975 Nov;115(5):1330–1338. [PubMed] [Google Scholar]
  29. Schwartz R. H., Paul W. E. T-lymphocyte-enriched murine peritoneal exudate cells. II. Genetic control of antigen-induced T-lymphocyte proliferation. J Exp Med. 1976 Mar 1;143(3):529–540. doi: 10.1084/jem.143.3.529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schwartz R. H., Solinger A. M., Ultee M., Margoliash E. Genetic control of the T-lymphocyte proliferative response to cytochrome c. Adv Exp Med Biol. 1978;98:371–386. doi: 10.1007/978-1-4615-8858-0_20. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Sprent J., Boehmer H. V., Nabholz M. Association of immunity and tolerance to host H-2 determinants in irradiated F1 hybrid mice reconstituted with bone marrow cells from one parental strain. J Exp Med. 1975 Aug 1;142(2):321–331. doi: 10.1084/jem.142.2.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Waldron J. A., Jr, Horn R. G., Rosenthal A. S. Antigen-induced proliferation of guinea pig lymphocytes in vitro: obligatory role of macrophages in the recognition of antigen by immune T-lymphocytes. J Immunol. 1973 Jul;111(1):58–64. [PubMed] [Google Scholar]
  34. Warner C. M., McIvor J. L., Maurer P. H., Merryman C. F. The immune response of allophenic mice to the synthetic polymer L-glutamic acid, L-lysine, L-phenylalanine. II. Lack of gene complementation in two nonresponder strains. J Exp Med. 1977 Mar 1;145(3):766–771. doi: 10.1084/jem.145.3.766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yano A., Schwartz R. H., Paul W. E. Antigen presentation in the murine T lymphocyte proliferative response. II. Ir-GAT-controlled T lymphocyte responses require antigen-presenting cells from a high responder donor. Eur J Immunol. 1978 May;8(5):344–347. doi: 10.1002/eji.1830080510. [DOI] [PubMed] [Google Scholar]
  36. Yano A., Schwartz R. H., Paul W. E. Antigen presentation in the murine T-lymphocyte proliferative response. I. Requirement for genetic identity at the major histocompatibility complex. J Exp Med. 1977 Sep 1;146(3):828–843. doi: 10.1084/jem.146.3.828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. 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]
  38. Zinkernagel R. M., Callahan G. N., Althage A., Cooper S., Streilein J. W., Klein J. The lymphoreticular system in triggering virus plus self-specific cytotoxic T cells: evidence for T help. J Exp Med. 1978 Mar 1;147(3):897–911. doi: 10.1084/jem.147.3.897. [DOI] [PMC free article] [PubMed] [Google Scholar]

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