Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Sep 15;90(18):8415–8419. doi: 10.1073/pnas.90.18.8415

Gamma delta T cells differentiate into a functional but nonproliferative state during a normal immune response.

D Spaner 1, K Migita 1, A Ochi 1, J Shannon 1, R G Miller 1, P Pereira 1, S Tonegawa 1, R A Phillips 1
PMCID: PMC47367  PMID: 8378313

Abstract

To obtain a homogeneous population of gamma delta T cells to investigate their role in an immune response, we have made a scid mouse doubly transgenic for rearranged gamma and delta genes. The receptor (KN6) encoded by these genes is specific for the major histocompatibility complex class I protein encoded by the T22b gene. This mouse contains high levels of transgenic gamma delta T cells in the spleen and thymus and no other T lymphocytes. Immunization of these KN6-scid (H-2d, TLd) mice with 10(7) C57BL/6J (abbreviated B6) (H-2b, TLb) spleen cells resulted in proliferation and activation of the gamma delta T cells in spleen and clearing of the allogeneic B6 lymphocytes. Subsequently, the majority of activated cells died by apoptosis and the remaining cells were anergic with regard to proliferation. The anergic cells did not respond to restimulation by B6 spleen cells in vitro or in vivo, and addition of exogenous interleukin 2 failed to restore the response to B6 cells. Cytotoxicity, a property of KN6+ cells during a primary stimulation, was no longer detectable in the proliferatively anergic cells. However, B6 spleen cells injected into mice primed 12 days previously were cleared with a much greater efficiency than on primary challenge and in an antigen-specific manner. We conclude that after exposure to antigen, gamma delta T cells rapidly proliferate into blasts; the majority of the blasts rapidly die, with the nonproliferating cells remaining in a highly active state for several weeks and able to initiate elimination of lymphoid cells bearing the TLb epitope.

Full text

PDF
8415

Images in this article

8417Fig. 2
on p.8417

Selected References

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

  1. Bandeira A., Mengel J., Burlen-Defranoux O., Coutinho A. Proliferative T cell anergy to MIs-1a does not correlate with in vivo tolerance. Int Immunol. 1991 Sep;3(9):923–931. doi: 10.1093/intimm/3.9.923. [DOI] [PubMed] [Google Scholar]
  2. Bonneville M., Ishida I., Itohara S., Verbeek S., Berns A., Kanagawa O., Haas W., Tonegawa S. Self-tolerance to transgenic gamma delta T cells by intrathymic inactivation. Nature. 1990 Mar 8;344(6262):163–165. doi: 10.1038/344163a0. [DOI] [PubMed] [Google Scholar]
  3. Bonneville M., Ito K., Krecko E. G., Itohara S., Kappes D., Ishida I., Kanagawa O., Janeway C. A., Murphy D. B., Tonegawa S. Recognition of a self major histocompatibility complex TL region product by gamma delta T-cell receptors. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5928–5932. doi: 10.1073/pnas.86.15.5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bonneville M., Itohara S., Krecko E. G., Mombaerts P., Ishida I., Katsuki M., Berns A., Farr A. G., Janeway C. A., Jr, Tonegawa S. Transgenic mice demonstrate that epithelial homing of gamma/delta T cells is determined by cell lineages independent of T cell receptor specificity. J Exp Med. 1990 Apr 1;171(4):1015–1026. doi: 10.1084/jem.171.4.1015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bosma G. C., Custer R. P., Bosma M. J. A severe combined immunodeficiency mutation in the mouse. Nature. 1983 Feb 10;301(5900):527–530. doi: 10.1038/301527a0. [DOI] [PubMed] [Google Scholar]
  6. Cohen C. J., Duke R. C., Sellins K. S. Stimulation by superantigen. Nature. 1991 Jul 18;352(6332):199–200. doi: 10.1038/352199b0. [DOI] [PubMed] [Google Scholar]
  7. Gershon R. K., Liebhaber S. A. The response of T cells to histocompatibility-2 antigens. Dose-response kinetics. J Exp Med. 1972 Jul 1;136(1):112–127. doi: 10.1084/jem.136.1.112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ito K., Van Kaer L., Bonneville M., Hsu S., Murphy D. B., Tonegawa S. Recognition of the product of a novel MHC TL region gene (27b) by a mouse gamma delta T cell receptor. Cell. 1990 Aug 10;62(3):549–561. doi: 10.1016/0092-8674(90)90019-b. [DOI] [PubMed] [Google Scholar]
  9. Itohara S., Farr A. G., Lafaille J. J., Bonneville M., Takagaki Y., Haas W., Tonegawa S. Homing of a gamma delta thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature. 1990 Feb 22;343(6260):754–757. doi: 10.1038/343754a0. [DOI] [PubMed] [Google Scholar]
  10. Itohara S., Nakanishi N., Kanagawa O., Kubo R., Tonegawa S. Monoclonal antibodies specific to native murine T-cell receptor gamma delta: analysis of gamma delta T cells during thymic ontogeny and in peripheral lymphoid organs. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5094–5098. doi: 10.1073/pnas.86.13.5094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Iwashima M., Davis M. M., Chien Y. H. A gamma/delta cell receptor heterodimer induces the expression of CD4 and CD8 in thymocytes. J Exp Med. 1991 Jul 1;174(1):293–296. doi: 10.1084/jem.174.1.293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kang S. M., Beverly B., Tran A. C., Brorson K., Schwartz R. H., Lenardo M. J. Transactivation by AP-1 is a molecular target of T cell clonal anergy. Science. 1992 Aug 21;257(5073):1134–1138. doi: 10.1126/science.257.5073.1134. [DOI] [PubMed] [Google Scholar]
  13. Karasuyama H., Melchers F. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. Eur J Immunol. 1988 Jan;18(1):97–104. doi: 10.1002/eji.1830180115. [DOI] [PubMed] [Google Scholar]
  14. Kawabe Y., Ochi A. Programmed cell death and extrathymic reduction of Vbeta8+ CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B. Nature. 1991 Jan 17;349(6306):245–248. doi: 10.1038/349245a0. [DOI] [PubMed] [Google Scholar]
  15. Kawabe Y., Ochi A. Selective anergy of V beta 8+,CD4+ T cells in Staphylococcus enterotoxin B-primed mice. J Exp Med. 1990 Oct 1;172(4):1065–1070. doi: 10.1084/jem.172.4.1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lenardo M. J. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature. 1991 Oct 31;353(6347):858–861. doi: 10.1038/353858a0. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Martin D. R., Miller R. G. In vivo administration of histoincompatible lymphocytes leads to rapid functional deletion of cytotoxic T lymphocyte precursors. J Exp Med. 1989 Sep 1;170(3):679–690. doi: 10.1084/jem.170.3.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Miller R. G., Dunkley M. Quantitative analysis of the 51Cr release cytotoxicity assay for cytotoxic lymphocytes. Cell Immunol. 1974 Nov;14(2):284–302. doi: 10.1016/0008-8749(74)90212-3. [DOI] [PubMed] [Google Scholar]
  20. Nabholz M., MacDonald H. R. Cytolytic T lymphocytes. Annu Rev Immunol. 1983;1:273–306. doi: 10.1146/annurev.iy.01.040183.001421. [DOI] [PubMed] [Google Scholar]
  21. Ramsdell F., Fowlkes B. J. Maintenance of in vivo tolerance by persistence of antigen. Science. 1992 Aug 21;257(5073):1130–1134. doi: 10.1126/science.257.5073.1130. [DOI] [PubMed] [Google Scholar]
  22. Rocha B., von Boehmer H. Peripheral selection of the T cell repertoire. Science. 1991 Mar 8;251(4998):1225–1228. doi: 10.1126/science.1900951. [DOI] [PubMed] [Google Scholar]
  23. Röcken M., Urban J. F., Shevach E. M. Infection breaks T-cell tolerance. Nature. 1992 Sep 3;359(6390):79–82. doi: 10.1038/359079a0. [DOI] [PubMed] [Google Scholar]
  24. Schuler W., Weiler I. J., Schuler A., Phillips R. A., Rosenberg N., Mak T. W., Kearney J. F., Perry R. P., Bosma M. J. Rearrangement of antigen receptor genes is defective in mice with severe combined immune deficiency. Cell. 1986 Sep 26;46(7):963–972. doi: 10.1016/0092-8674(86)90695-1. [DOI] [PubMed] [Google Scholar]
  25. Schönrich G., Kalinke U., Momburg F., Malissen M., Schmitt-Verhulst A. M., Malissen B., Hämmerling G. J., Arnold B. Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell. 1991 Apr 19;65(2):293–304. doi: 10.1016/0092-8674(91)90163-s. [DOI] [PubMed] [Google Scholar]
  26. Scott B., Blüthmann H., Teh H. S., von Boehmer H. The generation of mature T cells requires interaction of the alpha beta T-cell receptor with major histocompatibility antigens. Nature. 1989 Apr 13;338(6216):591–593. doi: 10.1038/338591a0. [DOI] [PubMed] [Google Scholar]
  27. Sinha A. A., Lopez M. T., McDevitt H. O. Autoimmune diseases: the failure of self tolerance. Science. 1990 Jun 15;248(4961):1380–1388. doi: 10.1126/science.1972595. [DOI] [PubMed] [Google Scholar]
  28. Sprent J. Fate of H2-activated T lymphocytes in syngeneic hosts. I. Fate in lymphoid tissues and intestines traced with 3H-thymidine, 125I-deoxyuridine and 51chromium. Cell Immunol. 1976 Feb;21(2):278–302. doi: 10.1016/0008-8749(76)90057-5. [DOI] [PubMed] [Google Scholar]
  29. Vitetta E. S., Berton M. T., Burger C., Kepron M., Lee W. T., Yin X. M. Memory B and T cells. Annu Rev Immunol. 1991;9:193–217. doi: 10.1146/annurev.iy.09.040191.001205. [DOI] [PubMed] [Google Scholar]
  30. Webb S., Morris C., Sprent J. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell. 1990 Dec 21;63(6):1249–1256. doi: 10.1016/0092-8674(90)90420-j. [DOI] [PubMed] [Google Scholar]
  31. Yancopoulos G. D., Alt F. W. Reconstruction of an immune system. Science. 1988 Sep 23;241(4873):1581–1583. doi: 10.1126/science.241.4873.1581. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES