Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1978 Mar 1;147(3):882–896. doi: 10.1084/jem.147.3.882

On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition?

PMCID: PMC2184211  PMID: 305459

Abstract

In the thymus, precursor T cells differentiate recognition structures for self that are specific for the H-2K, D, and I markers expressed by the thymic epithelium. Thus recognition of self-H-2 differentiates independently of the T cells H-2 type and independently of recognition of nonself antigen X. This is readily compatible with dual recognition by T cells but does not formally exclude a single recognition model. These conclusions derive from experiments with bone marrow and thymic chimeras. Irradiated mice reconstituted with bone marrow to form chimeras of (A X B)F1 leads to A type generate virus-specific cytotoxic T cells for infected targets A only. Therefore, the H-2 type of the host determines the H-2-restricted activity of killer T cells alone. In contrast, chimeras made by reconstituting irradiated A mice with adult spleen cells of (A X B)F1 origin generate virus-specific cytotoxic activity for infected A and B targets, suggesting that mature T cells do not change their self-specificity readily. (A X B)F1 leads to (A X C)F1 and (KAIA/DC) leads to (KAIA/DB) irradiation bone marrow chimeras responded against infected A but not B or C targets. This suggests that cytotoxicity is not generated against DC because it is abscent from the host's thymus epithelium and not against DB because it is not expressed by the reconstituting lymphoreticular system. (KBIB/DA) leads to (KCIC/DA) K, I incompatible, or completely H-2 incompatible A leads to B chimeras fail to generate any measurable virus specific cytotoxicity, indicating the necessity for I-specific helper T cells for the generation of killer T cells. Finally adult thymectomized, irradiated and bone marrow reconstituted (A X B)F1 mice, transplanted with an irradiated thymus of A origin, generate virus-specific cytotoxic T cells specific for infected A targets but not for B targets; this result formally demonstrates the crucial role of thymic epithelial cells in the differentiation of anti-self-H-2 specificities of T cells.

Full Text

The Full Text of this article is available as a PDF (1.0 MB).

Selected References

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

  1. Bechtol K. B., Freed J. H., Herzenberg L. A., McDevitt H. O. Genetic control of the antibody response to poly-L(Tyr,Glu)-poly-D,L-Ala--poly-L-Lys in C3H--CWB tetraparental mice. J Exp Med. 1974 Dec 1;140(6):1660–1675. doi: 10.1084/jem.140.6.1660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. 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]
  4. Callahan G. N., Ferrone S., Poulik M. D., Reisfeld R. A., Klein J. Characterization of Ia antigens in mouse serum. J Immunol. 1976 Oct;117(4):1351–1355. [PubMed] [Google Scholar]
  5. Davies A. J. The thymus and the cellular basis of immunity. Transplant Rev. 1969;1:43–91. doi: 10.1111/j.1600-065x.1969.tb00136.x. [DOI] [PubMed] [Google Scholar]
  6. Doherty P. C., Blanden R. V., Zinkernagel R. M. Specificity of virus-immune effector T cells for H-2K or H-2D compatible interactions: implications for H-antigen diversity. Transplant Rev. 1976;29:89–124. doi: 10.1111/j.1600-065x.1976.tb00198.x. [DOI] [PubMed] [Google Scholar]
  7. Editorial: Defective thymus development: a cause of combined immunodeficiency. N Engl J Med. 1975 Aug 28;293(9):450–451. doi: 10.1056/NEJM197508282930911. [DOI] [PubMed] [Google Scholar]
  8. Githens J. H. Editorial: Immunologic reconstitution with fetal tissue. N Engl J Med. 1976 May 13;294(20):1116–1117. doi: 10.1056/NEJM197605132942011. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Goulmy E., Termijtelen A., Bradley B. A., van Rood J. J. Y-antigen killing by T cells of women is restricted by HLA. Nature. 1977 Apr 7;266(5602):544–545. doi: 10.1038/266544a0. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. 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]
  14. Katz D. H., Hamaoka T., Benacerraf B. Cell interactions between histoincompatible T and B lymphocytes. II. Failure of physiologic cooperative interactions between T and B lymphocytes from allogeneic donor strains in humoral response to hapten-protein conjugates. J Exp Med. 1973 Jun 1;137(6):1405–1418. doi: 10.1084/jem.137.6.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Katz D. H. The role of the histocompatibilty gene complex in lymphocyte defferetiation. Cold Spring Harb Symp Quant Biol. 1977;41(Pt 2):611–624. doi: 10.1101/sqb.1977.041.01.070. [DOI] [PubMed] [Google Scholar]
  16. Miller J. F., Osoba D. Current concepts of the immunological function of the thymus. Physiol Rev. 1967 Jul;47(3):437–520. doi: 10.1152/physrev.1967.47.3.437. [DOI] [PubMed] [Google Scholar]
  17. Miller J. F., Vadas M. A., Whitelaw A., Gamble J. H-2 gene complex restricts transfer of delayed-type hypersensitivity in mice. Proc Natl Acad Sci U S A. 1975 Dec;72(12):5095–5098. doi: 10.1073/pnas.72.12.5095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pahwa R., Pahwa S., Good R. A., Incefy G. S., O'Reilly R. J. Rationale for combined use of fetal liver and thymus for immunological reconstitution in patients with variants of severe combined immunodeficiency. Proc Natl Acad Sci U S A. 1977 Jul;74(7):3002–3005. doi: 10.1073/pnas.74.7.3002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Paul W. E., Shevach E. M., Thomas D. W., Pickeral S. F., Rosenthal A. S. Genetic restriction in T-lymphocyte activation by antigen-pulse peritoneal exudate cells. Cold Spring Harb Symp Quant Biol. 1977;41(Pt 2):571–578. doi: 10.1101/sqb.1977.041.01.066. [DOI] [PubMed] [Google Scholar]
  20. Pfizenmaier K., Strazinski-Powitz A., Rodt H., Röllinghoff M., Wagner H. Virus and trinitrophenol hapten-specific T-cell-mediated cytotoxicity against H-2 incompatible target cells. J Exp Med. 1976 Apr 1;143(4):999–1004. doi: 10.1084/jem.143.4.999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ramseier H., Aguet M., Lindenmann J. Similarity of idiotypic determinants of T-and B-lymphocyte receptors for alloantigens. Immunol Rev. 1977;34:50–88. doi: 10.1111/j.1600-065x.1977.tb00368.x. [DOI] [PubMed] [Google Scholar]
  22. Rosenthal A. S., Shevach E. M. Function of macrophages in antigen recognition by guinea pig T lymphocytes. I. Requirement for histocompatible macrophages and lymphocytes. J Exp Med. 1973 Nov 1;138(5):1194–1212. doi: 10.1084/jem.138.5.1194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Shearer G. M., Rehn T. G., Schmitt-Verhulst A. M. Role of the murine major histocompatibility complex in the specificity of in vitro T-cell-mediated lympholysis against chemically-modified autologous lymphocytes. Transplant Rev. 1976;29:222–246. doi: 10.1111/j.1600-065x.1976.tb00203.x. [DOI] [PubMed] [Google Scholar]
  24. Shevach E. M., Rosenthal A. S. Function of macrophages in antigen recognition by guinea pig T lymphocytes. II. Role of the macrophage in the regulation of genetic control of the immune response. J Exp Med. 1973 Nov 1;138(5):1213–1229. doi: 10.1084/jem.138.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Toivanen P., Toivanen A., Vainio O. Complete restoration of bursa-dependent immune system after transplantation of semiallogeneic stem cells into immunodeficient chicks. J Exp Med. 1974 May 1;139(5):1344–1349. doi: 10.1084/jem.139.5.1344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Zinkernagel R. M., Althage A., Jensen F. C. Cell-mediated immune response to lymphocytic choriomeningitis and vaccinia virus in rats. J Immunol. 1977 Oct;119(4):1242–1247. [PubMed] [Google Scholar]
  28. Zinkernagel R. M., Callahan G. N., Streilein J. W., Klein J. Neonatally tolerant mice fail to react against virus-infected tolerated cells. Nature. 1977 Apr 28;266(5605):837–839. doi: 10.1038/266837a0. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Zinkernagel R. M., Doherty P. C. Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis. Nature. 1974 Oct 11;251(5475):547–548. doi: 10.1038/251547a0. [DOI] [PubMed] [Google Scholar]
  31. Zinkernagel R. M., Doherty P. C. The concept that surveillance of self is mediated via the same set of genes that determines recognition of allogenic cells. Cold Spring Harb Symp Quant Biol. 1977;41(Pt 2):505–510. doi: 10.1101/sqb.1977.041.01.058. [DOI] [PubMed] [Google Scholar]
  32. Zinkernagel R. M. H-2 restriction of virus-specific cytotoxicity across the H-2 barrier. Separate effector T-cell specificities are associated with self-H-2 and with the tolerated allogeneic H-2 in chimeras. J Exp Med. 1976 Oct 1;144(4):933–945. doi: 10.1084/jem.144.4.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. von Boehmer H., Hudson L., Sprent J. Collaboration of histoincompatible T and B lymphocytes using cells from tetraparental bone marrow chimeras. J Exp Med. 1975 Oct 1;142(4):989–997. doi: 10.1084/jem.142.4.989. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES