Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1989 May 1;169(5):1619–1630. doi: 10.1084/jem.169.5.1619

Preferential differentiation of T cell receptor specificities based on the MHC glycoproteins encountered during development. Evidence for positive selection

PMCID: PMC2189321  PMID: 2785580

Abstract

T cells recognize foreign antigens together with those MHC glycoproteins they have encountered during their development in the thymus. How the repertoire of antigen-specific TCRs is selected has not yet been fully defined. We have investigated the T cell repertoire specificities of CD4-CD8+ cytotoxic T cells developing under conditions where one of the class I MHC-encoded molecules is blocked, while other class I-MHC glycoproteins are still expressed. We show that antigen- specific T cells restricted to the blocked class I fail to develop, while generation of other class I-specific T cell proceeds undisturbed. This highly selective perturbation of the T cell receptor repertoire demonstrates that development of CD4-CD8+ T cells with a certain TCR specificity requires expression of particular alleles of class I MHC. Thus, TCR-MHC interactions provide signals essential to the differentiation of precursor T cells.

Full Text

The Full Text of this article is available as a PDF (800.3 KB).

Selected References

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

  1. Allison J. P., McIntyre B. W., Bloch D. Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody. J Immunol. 1982 Nov;129(5):2293–2300. [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. Ceredig R., Glasebrook A. L., MacDonald H. R. Phenotypic and functional properties of murine thymocytes. I. Precursors of cytolytic T lymphocytes and interleukin 2-producing cells are all contained within a subpopulation of "mature" thymocytes as analyzed by monoclonal antibodies and flow microfluorometry. J Exp Med. 1982 Feb 1;155(2):358–379. doi: 10.1084/jem.155.2.358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dembić Z., Haas W., Weiss S., McCubrey J., Kiefer H., von Boehmer H., Steinmetz M. Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature. 1986 Mar 20;320(6059):232–238. doi: 10.1038/320232a0. [DOI] [PubMed] [Google Scholar]
  5. Dialynas D. P., Quan Z. S., Wall K. A., Pierres A., Quintáns J., Loken M. R., Pierres M., Fitch F. W. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J Immunol. 1983 Nov;131(5):2445–2451. [PubMed] [Google Scholar]
  6. Fowlkes B. J., Schwartz R. H., Pardoll D. M. Deletion of self-reactive thymocytes occurs at a CD4+8+ precursor stage. Nature. 1988 Aug 18;334(6183):620–623. doi: 10.1038/334620a0. [DOI] [PubMed] [Google Scholar]
  7. Haskins K., Kubo R., White J., Pigeon M., Kappler J., Marrack P. The major histocompatibility complex-restricted antigen receptor on T cells. I. Isolation with a monoclonal antibody. J Exp Med. 1983 Apr 1;157(4):1149–1169. doi: 10.1084/jem.157.4.1149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Jenkinson E. J., Jhittay P., Kingston R., Owen J. J. Studies of the role of the thymic environment in the induction of tolerance to MHC antigens. Transplantation. 1985 Mar;39(3):331–333. doi: 10.1097/00007890-198503000-00030. [DOI] [PubMed] [Google Scholar]
  9. Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
  10. Kappler J. W., Wade T., White J., Kushnir E., Blackman M., Bill J., Roehm N., Marrack P. A T cell receptor V beta segment that imparts reactivity to a class II major histocompatibility complex product. Cell. 1987 Apr 24;49(2):263–271. doi: 10.1016/0092-8674(87)90567-8. [DOI] [PubMed] [Google Scholar]
  11. Kisielow P., Blüthmann H., Staerz U. D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. doi: 10.1038/333742a0. [DOI] [PubMed] [Google Scholar]
  12. Kisielow P., Teh H. S., Blüthmann H., von Boehmer H. Positive selection of antigen-specific T cells in thymus by restricting MHC molecules. Nature. 1988 Oct 20;335(6192):730–733. doi: 10.1038/335730a0. [DOI] [PubMed] [Google Scholar]
  13. Kruisbeek A. M., Mond J. J., Fowlkes B. J., Carmen J. A., Bridges S., Longo D. L. Absence of the Lyt-2-,L3T4+ lineage of T cells in mice treated neonatally with anti-I-A correlates with absence of intrathymic I-A-bearing antigen-presenting cell function. J Exp Med. 1985 May 1;161(5):1029–1047. doi: 10.1084/jem.161.5.1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kruisbeek A. M., Titus J. A., Stephany D. A., Gause B. L., Longo D. L. In vivo treatment with monoclonal anti-I-A antibodies: disappearance of splenic antigen-presenting cell function concomitant with modulation of splenic cell surface I-A and I-E antigens. J Immunol. 1985 Jun;134(6):3605–3614. [PubMed] [Google Scholar]
  15. Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Levy R. B., Shearer G. M. Regulation of T-cell-mediated lympholysis by the murine major histocompatibility complex. I. Preferential in vitro responses to trinitrophenyl-modified self K- and D-coded gene products in parental and F1 hybrid mouse strains. J Exp Med. 1979 Jun 1;149(6):1379–1392. doi: 10.1084/jem.149.6.1379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lo D., Ron Y., Sprent J. Induction of MHC-restricted specificity and tolerance in the thymus. Immunol Res. 1986;5(3):221–232. doi: 10.1007/BF02919203. [DOI] [PubMed] [Google Scholar]
  18. Marrack P., Kappler J. T cells can distinguish between allogeneic major histocompatibility complex products on different cell types. Nature. 1988 Apr 28;332(6167):840–843. doi: 10.1038/332840a0. [DOI] [PubMed] [Google Scholar]
  19. Marrack P., Kushnir E., Born W., McDuffie M., Kappler J. The development of helper T cell precursors in mouse thymus. J Immunol. 1988 Apr 15;140(8):2508–2514. [PubMed] [Google Scholar]
  20. Marrack P., Lo D., Brinster R., Palmiter R., Burkly L., Flavell R. H., Kappler J. The effect of thymus environment on T cell development and tolerance. Cell. 1988 May 20;53(4):627–634. doi: 10.1016/0092-8674(88)90578-8. [DOI] [PubMed] [Google Scholar]
  21. Maruŝić-Galesić S., Stephany D. A., Longo D. L., Kruisbeek A. M. Development of CD4-CD8+ cytotoxic T cells requires interactions with class I MHC determinants. Nature. 1988 May 12;333(6169):180–183. doi: 10.1038/333180a0. [DOI] [PubMed] [Google Scholar]
  22. Meuer S. C., Fitzgerald K. A., Hussey R. E., Hodgdon J. C., Schlossman S. F., Reinherz E. L. Clonotypic structures involved in antigen-specific human T cell function. Relationship to the T3 molecular complex. J Exp Med. 1983 Feb 1;157(2):705–719. doi: 10.1084/jem.157.2.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Ozato K., Mayer N. M., Sachs D. H. Monoclonal antibodies to mouse major histocompatibility complex antigens. Transplantation. 1982 Sep;34(3):113–120. doi: 10.1097/00007890-198209000-00001. [DOI] [PubMed] [Google Scholar]
  25. Saito T., Weiss A., Miller J., Norcross M. A., Germain R. N. Specific antigen-Ia activation of transfected human T cells expressing murine Ti alpha beta-human T3 receptor complexes. Nature. 1987 Jan 8;325(7000):125–130. doi: 10.1038/325125a0. [DOI] [PubMed] [Google Scholar]
  26. Samelson L. E., Harford J. B., Klausner R. D. Identification of the components of the murine T cell antigen receptor complex. Cell. 1985 Nov;43(1):223–231. doi: 10.1016/0092-8674(85)90027-3. [DOI] [PubMed] [Google Scholar]
  27. Sha W. C., Nelson C. A., Newberry R. D., Kranz D. M., Russell J. H., Loh D. Y. Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic mice. Nature. 1988 Sep 15;335(6187):271–274. doi: 10.1038/335271a0. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Singer A. Experimentation and thymic selection. J Immunol. 1988 Apr 15;140(8):2481–2483. [PubMed] [Google Scholar]
  30. Singer A., Hathcock K. S., Hodes R. J. Self recognition in allogeneic thymic chimeras. Self recognition by T helper cells from thymus-engrafted nude mice is restricted to the thymic H-2 haplotype. J Exp Med. 1982 Jan 1;155(1):339–344. doi: 10.1084/jem.155.1.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Singer A., Munitz T. I., Gress R. E. Specificity of thymic selection and the role of self antigens. Transplant Proc. 1987 Dec;19(6 Suppl 7):107–110. [PubMed] [Google Scholar]
  32. Sprent J., Lo D., Gao E. K., Ron Y. T cell selection in the thymus. Immunol Rev. 1988 Jan;101:173–190. doi: 10.1111/j.1600-065x.1988.tb00737.x. [DOI] [PubMed] [Google Scholar]
  33. Swain S. L. T cell subsets and the recognition of MHC class. Immunol Rev. 1983;74:129–142. doi: 10.1111/j.1600-065x.1983.tb01087.x. [DOI] [PubMed] [Google Scholar]
  34. Teh H. S., Kisielow P., Scott B., Kishi H., Uematsu Y., Blüthmann H., von Boehmer H. Thymic major histocompatibility complex antigens and the alpha beta T-cell receptor determine the CD4/CD8 phenotype of T cells. Nature. 1988 Sep 15;335(6187):229–233. doi: 10.1038/335229a0. [DOI] [PubMed] [Google Scholar]
  35. Von Boehmer H., Schubiger K. Thymocytes appear to ignore class I major histocompatibility complex antigens expressed on thymus epithelial cells. Eur J Immunol. 1984 Nov;14(11):1048–1052. doi: 10.1002/eji.1830141116. [DOI] [PubMed] [Google Scholar]
  36. Weiss A., Imboden J., Shoback D., Stobo J. Role of T3 surface molecules in human T-cell activation: T3-dependent activation results in an increase in cytoplasmic free calcium. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4169–4173. doi: 10.1073/pnas.81.13.4169. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES