Antigen-inducible, H-2-restricted, interleukin-2-producing T cell hybridomas. Lack of independent antigen and H-2 recognition (original) (raw)

Abstract

We developed a method for production of antigen-specific, H-2-restricted T cell hybrids. The tumor cell partner in the fusions was itself a T cell hybrid, FS6-14.13.AG2 (or its derivatives), which could be induced to produce the growth factor, interleukin-2 (IL-2), in response to a challenge with concanavalin A, but had no known antigen specificity. The normal T cell partner in the fusions was a population of lymph node T cell blasts that had been highly enriched in antigen-specific, H-2-restricted T cells by in vivo immunization, followed by in vitro challenge with antigen and clonal expansion in IL-2-containing medium. These fusions produced hybrids that grew constitutively in culture. A sizable proportion of the hybrids demonstrated the ability to produce IL-2 in response to a challenge with specific antigen presented by irradiated spleen cells of the appropriate H-2 type. Four cloned antigen/H-2-specific hybrid lines were produced. AO-40.10 responded to chicken ovalbumin (OVA) when presented by I-A(k)-bearing cells. DC1.18.3 responded to the apo form of beef cytochrome c when presented with I-A(d). AODK-10.4 responded to keyhole limpet hemocyanin (KLH) presented with I-A (d). AODK-1.16 also responded to KLH presented by a product of the I region of H-2(d), but the data were consistent with either a product of the I-J-I-E(d) region or a combinatorial molecule with elements from both I-A(d) and I-E(d)/I-C(d). Coincidentally, AO-40.10 was shown to have an unexpected alloreactivity with a product of H-2(b) mapping to the K-I-A region. These hybrids should prove invaluable as sources of monoclonal material for the study of the receptor(s) on T cells with H-2-restricted antigen specificities. We also generated T cell hybrids with two antigen/H-2 specificities by fusing an azaguanine-resistant clone of AO-40.10 to normal T cells with a different antigen/H-2 specificity. Many of the hybrids retained reactivity to OVA plus H-2(a) and to the second antigen/H-2 combination. None reacted to either OVA plus the second H-2 type or to the second antigen plus H-2(a). One of these hybrids was successfully cloned to produce the line AOFK- 11.11.1. It retained the ability to recognize OVA plus I-A(k) inherited from one parent, and KLH plus IA(f) inherited from the other. It did not recognize OVA plus IA(f) or KLH plus I-A(k). These results have some bearing on models describing the nature of T cell receptors for antigen recognized in association with H-2 products. They do not support models in which antigen and H-2 are recognized separately by two independent T cell receptors.

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Selected References

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  1. Bevan M. J. Killer cells reactive to altered-self antigens can also be alloreactive. Proc Natl Acad Sci U S A. 1977 May;74(5):2094–2098. doi: 10.1073/pnas.74.5.2094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bevan M. J. The major histocompatibility complex determines susceptibility to cytotoxic T cells directed against minor histocompatibility antigens. J Exp Med. 1975 Dec 1;142(6):1349–1364. doi: 10.1084/jem.142.6.1349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Binz H., Wigzell H. Shared idiotypic determinants on B and T lymphocytes reactive against the same antigenic determinants. I. Demonstration of similar or identical idiotypes on IgG molecules and T-cell receptors with specificity for the same alloantigens. J Exp Med. 1975 Jul 1;142(1):197–211. doi: 10.1084/jem.142.1.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blanden R. V., Ada G. L. A dual recognition model for cytotoxic T cells based on thymic selection of precursors with low affinity for Self H-2 antigens. Scand J Immunol. 1978 Mar;7(3):181–190. doi: 10.1111/j.1365-3083.1978.tb00442.x. [DOI] [PubMed] [Google Scholar]
  5. Burakoff S. J., Finberg R., Glimcher L., Lemonnier F., Benacerraf B., Cantor H. The biologic significance of alloreactivity. The ontogeny of T-cell sets specific for alloantigens or modified self antigens. J Exp Med. 1978 Nov 1;148(5):1414–1422. doi: 10.1084/jem.148.5.1414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. Corradin G., Harbury H. A. Cleavage of cytochrome c with cyanogen bromide. Biochim Biophys Acta. 1970 Dec 22;221(3):489–496. doi: 10.1016/0005-2795(70)90219-9. [DOI] [PubMed] [Google Scholar]
  9. Eichmann K., Ben-Neriah Y., Hetzelberger D., Polke C., Givol D., Lonai P. Correlated expression of VH framework and VH idiotypic determinants on T helper cells and on functionally undefined T cells binding group A streptococcal carbohydrate. Eur J Immunol. 1980 Feb;10(2):105–112. doi: 10.1002/eji.1830100207. [DOI] [PubMed] [Google Scholar]
  10. Eichmann K., Rajewsky K. Induction of T and B cell immunity by anti-idiotypic antibody. Eur J Immunol. 1975 Oct;5(10):661–666. doi: 10.1002/eji.1830051002. [DOI] [PubMed] [Google Scholar]
  11. Emerson S. G., Murphy D. B., Cone R. E. Selective turnover and shedding of H-2K and H-2D antigens is controlled by the major histocompatibility complex. Implications for H-2-restricted recognition. J Exp Med. 1980 Oct 1;152(4):783–795. doi: 10.1084/jem.152.4.783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fisher W. R., Taniuchi H., Anfinsen C. B. On the role of heme in the formation of the structure of cytochrome c. J Biol Chem. 1973 May 10;248(9):3188–3195. [PubMed] [Google Scholar]
  13. Glasebrook A. L., Fitch F. W. Alloreactive cloned T cell lines. I. Interactions between cloned amplifier and cytolytic T cell lines. J Exp Med. 1980 Apr 1;151(4):876–895. doi: 10.1084/jem.151.4.876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gordon R. D., Simpson E., Samelson L. E. In vitro cell-mediated immune responses to the male specific(H-Y) antigen in mice. J Exp Med. 1975 Nov 1;142(5):1108–1120. doi: 10.1084/jem.142.5.1108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Harwell L., Skidmore B., Marrack P., Kappler J. Concanavalin A-inducible, interleukin-2-producing T cell hybridoma. J Exp Med. 1980 Oct 1;152(4):893–904. doi: 10.1084/jem.152.4.893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Heber-Katz E., Wilson D. B. Sheep red blood cell-specific helper activity in rat thoracic duct lymphocyte populations positively selected for reactivity to specific strong histocompatibility alloantigens. J Exp Med. 1976 Mar 1;143(3):701–706. doi: 10.1084/jem.143.3.701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hünig T., Bevan M. J. Self H-2 antigens influence the specificity of alloreactive cells. J Exp Med. 1980 May 1;151(5):1288–1298. doi: 10.1084/jem.151.5.1288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Jerne N. K. The somatic generation of immune recognition. Eur J Immunol. 1971 Jan;1(1):1–9. doi: 10.1002/eji.1830010102. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Kapp J. A., Araneo B. A., Clevinger B. L. Suppression of antibody and T cell proliferative responses to L-glutamic acid60-L-alanine30-L-tyrosine10 by a specific monoclonal T cell factor. J Exp Med. 1980 Jul 1;152(1):235–240. doi: 10.1084/jem.152.1.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kappler J. W., Marrack P. C. Helper T cells recognise antigen and macrophage surface components simultaneously. Nature. 1976 Aug 26;262(5571):797–799. doi: 10.1038/262797a0. [DOI] [PubMed] [Google Scholar]
  23. Katz D. H., Bechtold T. E., Altman A. Construction of T cell hybridomas secreting allogeneic effect factor. J Exp Med. 1980 Oct 1;152(4):956–968. doi: 10.1084/jem.152.4.956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Kontiainen S., Simpson E., Bohrer E., Beverley P. C., Herzenberg L. A., Fitzpatrick W. C., Vogt P., Torano A., McKenzie I. F., Feldmann M. T-cell lines producing antigen-specific suppressor factor. Nature. 1978 Aug 3;274(5670):477–480. doi: 10.1038/274477a0. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Mishell R. I., Dutton R. W. Immunization of dissociated spleen cell cultures from normal mice. J Exp Med. 1967 Sep 1;126(3):423–442. doi: 10.1084/jem.126.3.423. [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. 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]
  30. Schrier R. D., Skidmore B. J., Kurnick J. T., Goldstine S. N., Chiller J. M. Propagation of antigen-specific T cell helper function in vitro. J Immunol. 1979 Dec;123(6):2525–2531. [PubMed] [Google Scholar]
  31. Sprent J. Restricted helper function of F1 hybrid T cells positively selected to heterologous erythrocytes in irradiated parental strain mice. II. Evidence for restrictions affecting helper cell induction and T-B collaboration, both mapping to the K-end of the H-2 complex. J Exp Med. 1978 Apr 1;147(4):1159–1174. doi: 10.1084/jem.147.4.1159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Taniguchi M., Miller J. F. Specific suppressive factors produced by hybridomas derived from the fusion of enriched suppressor T cells and a T lymphoma cell line. J Exp Med. 1978 Aug 1;148(2):373–382. doi: 10.1084/jem.148.2.373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Taussig M. J., Corvalan J. R., Binns R. M., Holliman A. Production of an H--2-related suppressor factor by a hybrid T-cell line. Nature. 1979 Jan 25;277(5694):305–308. doi: 10.1038/277305a0. [DOI] [PubMed] [Google Scholar]
  34. Watson J. Continuous proliferation of murine antigen-specific helper T lymphocytes in culture. J Exp Med. 1979 Dec 1;150(6):1510–1519. doi: 10.1084/jem.150.6.1510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Weinberger J. Z., Germain R. N., Ju S. T., Greene M. I., Benacerraf B., Dorf M. E. Hapten-specific T-cell responses to 4-hydroxy-3-nitrophenyl acetyl. II. Demonstration of idiotypic determinants on suppressor T cells. J Exp Med. 1979 Oct 1;150(4):761–776. doi: 10.1084/jem.150.4.761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Zinkernagel R. M., Doherty P. C. H-2 compatability requirement for T-cell-mediated lysis of target cells infected with lymphocytic choriomeningitis virus. Different cytotoxic T-cell specificities are associated with structures coded for in H-2K or H-2D;. J Exp Med. 1975 Jun 1;141(6):1427–1436. doi: 10.1084/jem.141.6.1427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Zinkernagel R. M., Doherty P. C. Major transplantation antigens, viruses, and specificity of surveillance T cells. Contemp Top Immunobiol. 1977;7:179–220. doi: 10.1007/978-1-4684-3054-7_5. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. von Boehmer H., Hengartner H., Nabholz M., Lernhardt W., Schreier M. H., Haas W. Fine specificity of a continuously growing killer cell clone specific for H-Y antigen. Eur J Immunol. 1979 Aug;9(8):592–597. doi: 10.1002/eji.1830090804. [DOI] [PubMed] [Google Scholar]