Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1981 Mar 1;153(3):677–693. doi: 10.1084/jem.153.3.677

Antigen-specific T cell clones restricted to unique F(1) major histocompatibility complex determinants. Inhibition of proliferation with a monoclonal anti-Ia antibody

B Sredni, LA Matis, EA Lerner, WE Paul, RH Schwartz
PMCID: PMC2186099  PMID: 6166704

Abstract

The existence of T cells specific for soluble antigens in association with unique F(1) or recombinant major histocompatibility complex (MHC) gene products was first postulated from studies on the proliferative response of whole T cell populations to the antigen poly(Glu(55)Lys(36)Phe(9))(n) (GLφ). In this paper we use the newly developed technology of T lymphocyte cloning to establish unequivocally the existence of such cells specific for GLφ and to generalize their existence by showing that F(1)- specific cells can be isolated from T cell populations primed to poly(Glu(60)Ala(30)Tyr(10))(n) (GAT) where such clones represent only a minor subpopulation of cells. Gl.4b-primed B10.A(5R) and GAT-primed (B10.A × B10)F(1) lymph node T cells were cloned in soft agar, and the colonies that developed were picked and expanded in liquid culture. The GLφ-specific T cells were then recloned under conditions of high-plating efficiency to ensure that the final colonies originated from single cells. T cells from such rigorously cloned populations responded to stimulation with GILφ but only in the presence of nonimmune, irradiated spleen cells bearing (B10.A × B10)F(1) or the syngeneic B 10.A(5R) recombinant MHC haplotype. Spleen cells from either the B10 or B 10.A parental strains failed to support a proliferative response, even when added together. (B10 × B10.D2)F(1) and (B10 × B10.RIII)F(1) spleen cells also supported a proliferative response but (B10 × B10.Q)F(1) and (B10 X B10.S)F(1) spleen cells did not. These results suggested that the T cell clones were specific for GL[phi} in association with the β(AE)(b)-α(E) (k,d,r,) Ia molecule and that recognition required both gene products to be expressed in the same antigen-presenting cells. Support for this interpretation was obtained from inhibition experiments using the monoclonal antibody Y-17 specific for a determinant on the β(AE)(b)-αE Ia molecule. Y-17 completely inhibited the proliferative response of a GLφ-specific clone but had no effect on the response of either a PPD-specific or GAT-specific clone, both of which required the β(A)-α(A) Ia molecule as their restriction element. No evidence could be found for the involvement of suppressor T cells in this inhibition. We therefore conclude that the phenomenon of F(1)-restricted recognition by proliferating T cells results from the presence of antigen- specific clones that must recognize unique F(1) or recombinant Ia molecules on the surface of antigen-presenting cells in addition to antigen in order to be stimulated.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

Selected References

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

  1. Baker P. E., Gillis S., Smith K. A. Monoclonal cytolytic T-cell lines. J Exp Med. 1979 Jan 1;149(1):273–278. doi: 10.1084/jem.149.1.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Broder S., Mann D. L., Waldmann T. A. Participation of suppressor T cells in the immunosuppressive activity of a heteroantiserum to human Ia-like antigens (p23,30). J Exp Med. 1980 Jan 1;151(1):257–262. doi: 10.1084/jem.151.1.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burger R., Shevach E. M. Monoclonal antibodies to guinea pig Ia antigens. II. Effect on alloantigen-, antigen-, and mitogen-induced T lymphocyte proliferation in vitro. J Exp Med. 1980 Oct 1;152(4):1011–1023. doi: 10.1084/jem.152.4.1011. [DOI] [PMC free article] [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. Cook R. G., Vitetta E. S., Uhr J. W., Capra J. D. Structural studies on the murine Ia alloantigens--III. Tryptic peptide comparisons of allelic products of the I-E/C sub-region. Mol Immunol. 1979 Jan;16(1):29–35. doi: 10.1016/0161-5890(79)90024-5. [DOI] [PubMed] [Google Scholar]
  7. Cook R. G., Vitetta E. S., Uhr J. W., Capra J. D. Structural studies on the murine Ia alloantigens. V. Evidence that the structural gene for the I-E/C beta polypeptide is encoded within the I-A subregion. J Exp Med. 1979 Apr 1;149(4):981–986. doi: 10.1084/jem.149.4.981. [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. 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]
  10. Freed J. H., Sears D. W., Brown J. L., Nathenson S. G. Biochemical purification of detergent-solubilized H-2 alloantigens. Mol Immunol. 1979 Jan;16(1):9–21. doi: 10.1016/0161-5890(79)90022-1. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Hengartner H., Fathman C. G. Clones of alloreactive T cells. I. A. unique homozygous MLR-stimulating determinant present on B6 stimulators. Immunogenetics. 1980;10(2):175–184. doi: 10.1007/BF01561566. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. 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]
  16. Kimoto M., Fathman C. G. Antigen-reactive T cell clones. I. Transcomplementing hybrid I-A-region gene products function effectively in antigen presentation. J Exp Med. 1980 Oct 1;152(4):759–770. doi: 10.1084/jem.152.4.759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Longo D. L., Schwartz R. H. Gene complementation. Neither Ir-GLphi gene need be present in the proliferative T cell to generate an immune response to Poly(Glu55Lys36Phe9)n. J Exp Med. 1980 Jun 1;151(6):1452–1467. doi: 10.1084/jem.151.6.1452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lotze M. T., Strausser J. L., Rosenberg S. A. In vitro growth of cytotoxic human lymphocytes. II. Use of T cell growth factor (TCGF) to clone human T cells. J Immunol. 1980 Jun;124(6):2972–2978. [PubMed] [Google Scholar]
  20. Lyons C. R., Tucker T. F., Uhr J. W. Specific binding of T lymphocytes to macrophages. V. The role of Ia antigens on Mphi in the binding. J Immunol. 1979 Apr;122(4):1598–1600. [PubMed] [Google Scholar]
  21. McMillan M., Cecka J. M., Hood L., Murphy D. B., McDevitt H. O. Peptide map analyses of murine Ia antigens of the I-E subregion using HPLC. Nature. 1979 Feb 22;277(5698):663–665. doi: 10.1038/277663a0. [DOI] [PubMed] [Google Scholar]
  22. Paul W. E., Shevach E. M., Pickeral S., Thomas D. W., Rosenthal A. S. Independent populations of primed F1 guinea pig T lymphocytes respond to antigen-pulsed parental peritoneal exudate cells. J Exp Med. 1977 Mar 1;145(3):618–630. doi: 10.1084/jem.145.3.618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rosenberg S. A., Spiess P. J., Schwarz S. In vitro growth of murine T cells. I. Production of factors necessary for T cell growth. J Immunol. 1978 Nov;121(5):1946–1950. [PubMed] [Google Scholar]
  24. 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]
  25. Schreier M. H., Tees R. Clonal induction of helper T cells: conversion of specific signals into nonspecific signals. Int Arch Allergy Appl Immunol. 1980;61(2):227–237. doi: 10.1159/000232437. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Schwartz R. H., Chen C., Paul W. E. Gene complementation in the T lymphocyte proliferative response to poly (Glu56Lys35Phe9)n. Functional evidence for a restriction element coded for by both the I-A and I-E subregions. Eur J Immunol. 1980 Sep;10(9):708–714. doi: 10.1002/eji.1830100910. [DOI] [PubMed] [Google Scholar]
  28. Schwartz R. H., David C. S., Sachs D. H., Paul W. E. T lymphocyte-enriched murine peritoneal exudate cells. III. Inhibition of antigen-induced T lymphocyte Proliferation with anti-Ia antisera. J Immunol. 1976 Aug;117(2):531–540. [PubMed] [Google Scholar]
  29. 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]
  30. 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]
  31. Shevach E. M., Paul W. E., Green I. Histocompatibility-linked immune response gene function in guinea pigs. Specific inhibition of antigen-induced lymphocyte proliferation by alloantisera. J Exp Med. 1972 Nov 1;136(5):1207–1221. doi: 10.1084/jem.136.5.1207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Silver J. Trans gene complementation of I-E subregion antigens. J Immunol. 1979 Sep;123(3):1423–1425. [PubMed] [Google Scholar]
  33. Solinger A. M., Schwartz R. H. The T lymphocyte proliferative response to poly-L-Glu-poly-D,L-Ala--poly-L-Lys. J Immunol. 1980 May;124(5):2485–2490. [PubMed] [Google Scholar]
  34. Solinger A. M., Ultee M. E., Margoliash E., Schwartz R. H. T-lymphocyte response to cytochrome c. I. Demonstration of a T-cell heteroclitic proliferative response and identification of a topographic antigenic determinant on pigeon cytochrome c whose immune recognition requires two complementing major histocompatibility complex-linked immune response genes. J Exp Med. 1979 Oct 1;150(4):830–848. doi: 10.1084/jem.150.4.830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sprent J. Role of H-2 gene products in the function of T helper cells from normal and chimeric mice in vivo. Immunol Rev. 1978;42:108–137. doi: 10.1111/j.1600-065x.1978.tb00260.x. [DOI] [PubMed] [Google Scholar]
  36. Sproviero J. F., Imperiale M. J., Zauderer M. Clonal analysis of F1 hybrid helper T cells restricted to parental or F1 hybrid major histocompatibility determinants. J Exp Med. 1980 Oct 1;152(4):920–930. doi: 10.1084/jem.152.4.920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sredni B., Tse H. Y., Chen C., Schwartz R. H. Antigen-specific clones of proliferating T lymphocytes. I. Methodology, specificity, and MHC restriction. J Immunol. 1981 Jan;126(1):341–347. [PubMed] [Google Scholar]
  38. Sredni B., Tse H. Y., Schwartz R. H. Direct cloning and extended culture of antigen-specific MHC-restricted, proliferating T lymphocytes. Nature. 1980 Feb 7;283(5747):581–583. doi: 10.1038/283581a0. [DOI] [PubMed] [Google Scholar]
  39. Vaz N. M., de Souza C. M., Maia L. C. Genetic control of immune responsiveness in mice. Responsiveness to ovalbumin in (C57BL X DBA-2)F1 mice. Int Arch Allergy Appl Immunol. 1974;46(2):275–279. doi: 10.1159/000231130. [DOI] [PubMed] [Google Scholar]
  40. Werdelin O., Shevach E. M. Role of nominal antigen and Ia antigen in the binding of antigen-specific T lymphocytes to macrophages. J Immunol. 1979 Dec;123(6):2779–2784. [PubMed] [Google Scholar]
  41. 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]
  42. Zaleski M. B., Klein J. Immune response of mice to the Thy-1.1 antigen: intra-H-2 mapping of the complementary Ir-Thy-1 loci. J Immunol. 1976 Sep;117(3):814–817. [PubMed] [Google Scholar]
  43. Zaleski M., Milgrom F. Complementary genes controlling immune response to theta-AKR antigen in mice. J Immunol. 1973 May;110(5):1238–1244. [PubMed] [Google Scholar]
  44. 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]
  45. Zinkernagel R. M., Doherty P. C. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol. 1979;27:51–177. doi: 10.1016/s0065-2776(08)60262-x. [DOI] [PubMed] [Google Scholar]
  46. 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]
  47. 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]

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

RESOURCES