Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1981 Jun 1;153(6):1629–1639. doi: 10.1084/jem.153.6.1629

H-2 restriction as a consequence of intentional priming. Frequency analysis of alloantigen-restricted, trinitrophenyl-specific cytotoxic T lymphocyte precursors within thymocytes of normal mice

PMCID: PMC2186190  PMID: 6973002

Abstract

An in vitro acute-depletion protocol was used to detect trinitrophenyl (TNP)-specific, allo-major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) within thymocytes of inbred mice. After removal of alloreactivity, the negatively selected cells could be sensitized to become TNP-specific, allo-MHC-restricted cytotoxic T cells. A precursors frequency analysis revealed a three- to ninefold lower frequency of allo-MHC-restricted CTL precursors (CTL-P) as compared to self-MHC-restricted CTL-P. The specificity analysis of clonally distributed allo-MHC-restricted CTL-P excluded cross- reactivity as an explanation of allo-MHC restriction. These results provide direct evidence that thymic T cells are composed of a mixture of self-MHC- and allo-MHC-restricted immunocompetent T cells and that antigen-driven selection of precommitted T cells dictates the H-2- restriction phenotype, i.e., H-2 restriction is a consequence of priming.

Full Text

The Full Text of this article is available as a PDF (714.0 KB).

Selected References

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

  1. Ashman R. B., Müllbacher A. A T helper cell for anti-viral cytotoxic T-cell responses. J Exp Med. 1979 Nov 1;150(5):1277–1282. doi: 10.1084/jem.150.5.1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bevan M. J., Fink P. J. The influence of thymus H-2 antigens on the specificity of maturing killer and helper cells. Immunol Rev. 1978;42:3–19. doi: 10.1111/j.1600-065x.1978.tb00256.x. [DOI] [PubMed] [Google Scholar]
  3. Blanden R. V., Andrew M. E. Primary anti-viral cytotoxic T-cell responses in semiallogeneic chimeras are not absolutely restricted to host H-2 type. J Exp Med. 1979 Feb 1;149(2):535–538. doi: 10.1084/jem.149.2.535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Cooley M. A., Schmitt-Verhulst A. M. Specific helper T cells permit differentiation of thymic anti-self-trinitrophenyl cytotoxic precursor cells. J Immunol. 1979 Nov;123(5):2328–2336. [PubMed] [Google Scholar]
  6. Doherty P. C., Bennink J. C. Vaccinia-specific cytotoxic T-cell responses in the context of H-2 antigens not encountered in thymus may reflect aberrant recognition of a virus-H-2 complex. J Exp Med. 1979 Jan 1;149(1):150–157. doi: 10.1084/jem.149.1.150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Doherty P. C., Bennink J. R. An examination of MHC restriction in the context of a minimal clonal abortion model for self tolerance. Scand J Immunol. 1980;12(4):271–280. doi: 10.1111/j.1365-3083.1980.tb00067.x. [DOI] [PubMed] [Google Scholar]
  8. Forman J., Streilein J. W. T cells recognize minor histocompatibility antigens on H-2 allogeneic cells. J Exp Med. 1979 Oct 1;150(4):1001–1007. doi: 10.1084/jem.150.4.1001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gillis S., Union N. A., Baker P. E., Smith K. A. The in vitro generation and sustained culture of nude mouse cytolytic T-lymphocytes. J Exp Med. 1979 Jun 1;149(6):1460–1476. doi: 10.1084/jem.149.6.1460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hünig T., Bevan M. J. Specificity of cytotoxic T cells from athymic mice. J Exp Med. 1980 Sep 1;152(3):688–702. doi: 10.1084/jem.152.3.688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hünig T., Schimpl A. Studies on the generation and expression of H-2-controlled T helper function in chimeric mice: evidence for two levels of H-2 resitriction. Eur J Immunol. 1979 Sep;9(9):730–736. doi: 10.1002/eji.1830090912. [DOI] [PubMed] [Google Scholar]
  12. Janeway C. A., Jr, Murphy P. D., Kemp J., Wigzell H. T cells specific for hapten-modified self are precommitted for self major histocompatibility complex antigens before encounter with the hapten. J Exp Med. 1978 Apr 1;147(4):1065–1077. doi: 10.1084/jem.147.4.1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Matsunaga T., Simpson E. H-2 complementation in anti-H-Y cytotoxic T-cell responses can occur in chimeric mice. Proc Natl Acad Sci U S A. 1978 Dec;75(12):6207–6210. doi: 10.1073/pnas.75.12.6207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Matzinger P., Mirkwood G. In a fully H-2 incompatible chimera, T cells of donor origin can respond to minor histocompatibility antigens in association with either donor or host H-2 type. J Exp Med. 1978 Jul 1;148(1):84–92. doi: 10.1084/jem.148.1.84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Miller R. G. An immunological suppressor cell inactivating cytotoxic T-lymphocyte precursor cells recognizing it. Nature. 1980 Oct 9;287(5782):544–546. doi: 10.1038/287544a0. [DOI] [PubMed] [Google Scholar]
  16. Paetkau V., Shaw J., Mills G., Caplan B. Cellular origins and targets of costimulator (IL2). Immunol Rev. 1980;51:157–175. doi: 10.1111/j.1600-065x.1980.tb00320.x. [DOI] [PubMed] [Google Scholar]
  17. Pfizenmaier K., Delzeit R., Röllinghoff M., Wagner H. T-T cell interactions during in vitro cytotoxic T lymphocyte responses. III. Antigen-specific T helper cells release nonspecific mediator(s) able to help induction of H-2-restricted cytotoxic T lymphocyte responses across cell-impermeable membranes. Eur J Immunol. 1980 Aug;10(8):577–582. doi: 10.1002/eji.1830100802. [DOI] [PubMed] [Google Scholar]
  18. Shearer G. M., Schmitt-Verhulst A. M., Pettinelli C. B., Miller M. W., Gilheany P. E. H-2-linked genetic control of murine T-cell-mediated lympholysis to autologous cells modified with low concentrations of trinitrobenzene sulfonate. J Exp Med. 1979 Jun 1;149(6):1407–1423. doi: 10.1084/jem.149.6.1407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Starzinski-Powitz A., Pfizenmaier K., Röllinghoff M., Wagner H. In vivo sensitization of T cells to hapten-conjugated syngeneic structures of major histocompatibility complex. I. Effect of in vitro culture upon generation of cytotoxic T lymphocytes. Eur J Immunol. 1976 Nov;6(11):799–805. doi: 10.1002/eji.1830061109. [DOI] [PubMed] [Google Scholar]
  21. Stockinger H., Pfizenmaier K., Hardt C., Rodt H., Röllinghoff M., Wagner H. H-2 restriction as a consequence of intentional priming: T cells of fully allogeneic chimeric mice as well as of normal mice respond to foreign antigens in the context of H-2 determinants not encountered on thymic epithelial cells. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7390–7394. doi: 10.1073/pnas.77.12.7390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Taswell C., MacDonald H. R., Cerottini J. C. Limiting dilution analysis of alloantigen-reactive T lymphocytes. II. Effect of cortisone and cyclophosphamide on cytolytic T lymphocyte precursor frequencies in the thymus. Thymus. 1979 Sep;1(1-2):119–131. [PubMed] [Google Scholar]
  23. Teh H. S., Harley E., Phillips R. A., Miller R. G. Quantitative studies on the precursors of cytotoxic lymphocytes. I. Characterization of a clonal assay and determination of the size of clones derived from single precursors. J Immunol. 1977 Mar;118(3):1049–1056. [PubMed] [Google Scholar]
  24. Thomas D. W., Shevach E. M. Nature of the antigenic complex recognized by T lymphocytes: specific sensitization by antigens associated with allogeneic macrophages. Proc Natl Acad Sci U S A. 1977 May;74(5):2104–2108. doi: 10.1073/pnas.74.5.2104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Wagner H., Hardt C., Bartlett R., Stockinger H., Röllinghoff M., Rodt H., Pfizenmaier K. Frequency analysis of cytotoxic T lymphocyte precursors in chimeric mice. Evidence for intrathymic maturation of clonally distinct self-major histocompatibility complex- and allo-major histocompatiblilty complex-restricted virus-specific T cells. J Exp Med. 1981 Jun 1;153(6):1517–1532. doi: 10.1084/jem.153.6.1517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wagner H., Hardt C., Heeg K., Röllinghoff M., Pfizenmaier K. T-cell-derived helper factor allows in vivo induction of cytotoxic T cells in nu/nu mice. Nature. 1980 Mar 20;284(5753):278–278. doi: 10.1038/284278a0. [DOI] [PubMed] [Google Scholar]
  27. Wagner H., Röllinghoff M., Rodt H., Thierfelder S. T cell-mediated cytotoxic immune responsiveness of chimeric mice bearing a thymus graft fully allogeneic to the graft of lymphoid stem cells. Eur J Immunol. 1980 Jul;10(7):521–525. doi: 10.1002/eji.1830100707. [DOI] [PubMed] [Google Scholar]
  28. Wagner H., Röllinghoff M., Schawaller R., Hardt C., Pfizenmaier K. T-cell-derived helper factor allows Lyt 123 thymocytes to differentiate into cytotoxic T lymphocytes. Nature. 1979 Aug 2;280(5721):405–406. doi: 10.1038/280405a0. [DOI] [PubMed] [Google Scholar]
  29. Wagner H., Röllinghoff M. T-T-cell interactions during the vitro cytotoxic allograft responses. I. Soluble products from activated Lyl+ T cells trigger autonomously antigen-primed Ly23+ T cells to cell proliferation and cytolytic activity. J Exp Med. 1978 Dec 1;148(6):1523–1538. doi: 10.1084/jem.148.6.1523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Waldmann H. The influence of the major histocompatibility complex on the function of T-helper cells in antibody formation. Immunol Rev. 1978;42:202–223. doi: 10.1111/j.1600-065x.1978.tb00263.x. [DOI] [PubMed] [Google Scholar]
  31. Wilson D. B., Lindahl K. F., Wilson D. H., Sprent J. The generation of killer cells to trinitrophenyl-modified allogeneic targets by lymphocyte populations negatively selected to strong alloantigens. J Exp Med. 1977 Aug 1;146(2):361–367. doi: 10.1084/jem.146.2.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Zinkernagel R. M., Althage A., Cooper S., Callahan G., Klein J. In irradiation chimeras, K or D regions of the chimeric host, not of the donor lymphocytes, determine immune responsiveness of antiviral cytotoxic T cells. J Exp Med. 1978 Sep 1;148(3):805–810. doi: 10.1084/jem.148.3.805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zinkernagel R. M., Althage A. Search for suppression of T cells specific for the second nonhost H-2 haplotype in F1 leads to P irradiation bone marrow chimeras. J Immunol. 1979 May;122(5):1742–1749. [PubMed] [Google Scholar]
  34. Zinkernagel R. M. Thymus and lymphohemopoietic cells: their role in T cell maturation in selection of T cells' H-2-restriction-specificity and in H-2 linked Ir gene control. Immunol Rev. 1978;42:224–270. doi: 10.1111/j.1600-065x.1978.tb00264.x. [DOI] [PubMed] [Google Scholar]
  35. 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]

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

RESOURCES