Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1989 Jun 1;169(6):2149–2158. doi: 10.1084/jem.169.6.2149

Postnatal disappearance of self-reactive (V beta 6+) cells from the thymus of Mlsa mice. Implications for T cell development and autoimmunity

PMCID: PMC2189338  PMID: 2471774

Abstract

The postnatal ontogeny of potentially autoreactive T cells has been studied in a model system where a particular TCR beta chain variable domain (V beta 6) is correlated with reactivity to a minor antigen encoded by the Mlsa locus. Although absent among mature (CD4+ or CD8+) T cells in adult mice expressing Mlsa, brightly staining V beta 6+ cells were readily detectable in the thymus of neonatal animals, reaching a maximum after 4 d and decreasing rapidly thereafter. These V beta 6+ thymocytes were predominantly of the CD4+ phenotype and were localized in the medulla of the developing thymus. Furthermore, the intensity of TCR expression by these CD4+ cells was significantly (twofold) reduced as compared with age-matched Mlsb controls. A rapid disappearance of CD4+V beta 6+ cells (and corresponding decrease in TCR density) could also be observed in the thymus of Mlsb mice that had been injected neonatally with Mlsa spleen cells. Taken together, these results raise the possibility that some autoreactive T cells may persist after birth and that TCR downregulation may occur as a physiological response to tolerogenic signals in vivo.

Full Text

The Full Text of this article is available as a PDF (871.5 KB).

Selected References

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

  1. Ahmed A., Scher I. Studies on non-H-2-linked lymphocyte-activating determinants. II. Nonexpression of Mls determinants in a mouse strain with an X-linked B lymphocyte immune defect. J Immunol. 1976 Nov;117(5 PT2):1922–1926. [PubMed] [Google Scholar]
  2. BILLINGHAM R. E., BRENT L., MEDAWAR P. B. Actively acquired tolerance of foreign cells. Nature. 1953 Oct 3;172(4379):603–606. doi: 10.1038/172603a0. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Budd R. C., Schreyer M., Miescher G. C., MacDonald H. R. T cell lineages in the thymus of lpr/lpr mice. Evidence for parallel pathways of normal and abnormal T cell development. J Immunol. 1987 Oct 1;139(7):2200–2210. [PubMed] [Google Scholar]
  5. Cantrell D. A., Davies A. A., Crumpton M. J. Activators of protein kinase C down-regulate and phosphorylate the T3/T-cell antigen receptor complex of human T lymphocytes. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8158–8162. doi: 10.1073/pnas.82.23.8158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Festenstein H., Berumen L. BALB.D2-Mlsa--a new congenic mouse strain. Transplantation. 1984 Mar;37(3):322–324. doi: 10.1097/00007890-198403000-00024. [DOI] [PubMed] [Google Scholar]
  7. Fink P. J., Shimonkevitz R. P., Bevan M. J. Veto cells. Annu Rev Immunol. 1988;6:115–137. doi: 10.1146/annurev.iy.06.040188.000555. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Fry A. M., Matis L. A. Self-tolerance alters T-cell receptor expression in an antigen-specific MHC restricted immune response. Nature. 1988 Oct 27;335(6193):830–832. doi: 10.1038/335830a0. [DOI] [PubMed] [Google Scholar]
  10. Haskins K., Hannum C., White J., Roehm N., Kubo R., Kappler J., Marrack P. The antigen-specific, major histocompatibility complex-restricted receptor on T cells. VI. An antibody to a receptor allotype. J Exp Med. 1984 Aug 1;160(2):452–471. doi: 10.1084/jem.160.2.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hengartner H., Odermatt B., Schneider R., Schreyer M., Wälle G., MacDonald H. R., Zinkernagel R. M. Deletion of self-reactive T cells before entry into the thymus medulla. Nature. 1988 Nov 24;336(6197):388–390. doi: 10.1038/336388a0. [DOI] [PubMed] [Google Scholar]
  12. Hosono M., Kina T., Hosokawa T., Katsura Y. Neonatal tolerance induction in the thymus to MHC-class II-associated antigens. I. Preferential induction of tolerance to Mls antigens and resistance to allo-MHC antigens. Cell Immunol. 1986 Nov;103(1):1–10. doi: 10.1016/0008-8749(86)90062-6. [DOI] [PubMed] [Google Scholar]
  13. Howe M. L., Goldstein A. L., Battisto J. R. Isogeneic lymphocyte interaction: recognition of self antigens by cells of the neonatal thymus. Proc Natl Acad Sci U S A. 1970 Oct;67(2):613–619. doi: 10.1073/pnas.67.2.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Janeway C. A., Jr T-cell development. Accessories or coreceptors? Nature. 1988 Sep 15;335(6187):208–210. doi: 10.1038/335208a0. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. 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]
  17. 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]
  18. Landegren U. Measurement of cell numbers by means of the endogenous enzyme hexosaminidase. Applications to detection of lymphokines and cell surface antigens. J Immunol Methods. 1984 Mar 16;67(2):379–388. doi: 10.1016/0022-1759(84)90477-0. [DOI] [PubMed] [Google Scholar]
  19. Lattime E. C., Gillis S., Pecoraro G., Stutman O. Ia-dependent interleukin 2 production in syngeneic cellular interactions. J Immunol. 1982 Jan;128(1):480–485. [PubMed] [Google Scholar]
  20. MacDonald H. R., Glasebrook A. L., Schneider R., Lees R. K., Pircher H., Pedrazzini T., Kanagawa O., Nicolas J. F., Howe R. C., Zinkernagel R. M. T-cell reactivity and tolerance to Mlsa-encoded antigens. Immunol Rev. 1989 Feb;107:89–108. doi: 10.1111/j.1600-065x.1989.tb00004.x. [DOI] [PubMed] [Google Scholar]
  21. MacDonald H. R., Hengartner H., Pedrazzini T. Intrathymic deletion of self-reactive cells prevented by neonatal anti-CD4 antibody treatment. Nature. 1988 Sep 8;335(6186):174–176. doi: 10.1038/335174a0. [DOI] [PubMed] [Google Scholar]
  22. MacDonald H. R., Lees R. K., Schneider R., Zinkernagel R. M., Hengartner H. Positive selection of CD4+ thymocytes controlled by MHC class II gene products. Nature. 1988 Dec 1;336(6198):471–473. doi: 10.1038/336471a0. [DOI] [PubMed] [Google Scholar]
  23. MacDonald H. R., Pedrazzini T., Schneider R., Louis J. A., Zinkernagel R. M., Hengartner H. Intrathymic elimination of Mlsa-reactive (V beta 6+) cells during neonatal tolerance induction to Mlsa-encoded antigens. J Exp Med. 1988 Jun 1;167(6):2005–2010. doi: 10.1084/jem.167.6.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Macphail S., Ishizaka S. T., Bykowsky M. J., Lattime E. C., Stutman O. Specific neonatally induced tolerance to Mls locus determinants. J Immunol. 1985 Nov;135(5):2967–2974. [PubMed] [Google Scholar]
  25. 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]
  26. Nishizuka Y., Sakakura T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science. 1969 Nov 7;166(3906):753–755. doi: 10.1126/science.166.3906.753. [DOI] [PubMed] [Google Scholar]
  27. Nossal G. J. Cellular mechanisms of immunologic tolerance. Annu Rev Immunol. 1983;1:33–62. doi: 10.1146/annurev.iy.01.040183.000341. [DOI] [PubMed] [Google Scholar]
  28. Payne J., Huber B. T., Cannon N. A., Schneider R., Schilham M. W., Acha-Orbea H., MacDonald H. R., Hengartner H. Two monoclonal rat antibodies with specificity for the beta-chain variable region V beta 6 of the murine T-cell receptor. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7695–7698. doi: 10.1073/pnas.85.20.7695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Silverman D. A., Rose N. R. Neonatal thymectomy increases the incidence of spontaneous and methylcholanthrene-enhanced thyroiditis in rats. Science. 1974 Apr 12;184(4133):162–163. doi: 10.1126/science.184.4133.162. [DOI] [PubMed] [Google Scholar]
  30. Smith L. CD4+ murine T cells develop from CD8+ precursors in vivo. Nature. 1987 Apr 23;326(6115):798–800. doi: 10.1038/326798a0. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Taguchi O., Nishizuka Y. Experimental autoimmune orchitis after neonatal thymectomy in the mouse. Clin Exp Immunol. 1981 Nov;46(2):425–434. [PMC free article] [PubMed] [Google Scholar]
  33. Tung K. S., Smith S., Teuscher C., Cook C., Anderson R. E. Murine autoimmune oophoritis, epididymoorchitis, and gastritis induced by day 3 thymectomy. Immunopathology. Am J Pathol. 1987 Feb;126(2):293–302. [PMC free article] [PubMed] [Google Scholar]
  34. Yunis E. J., Hong R., Grewe M. A., Martinez C., Cornelius E., Good R. A. Postthymectomy wasting associated with autoimmune phenomena. I. Antiglobulin-positive anemia in A and C57BL-6 Ks mice. J Exp Med. 1967 May 1;125(5):947–966. doi: 10.1084/jem.125.5.947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. 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]
  36. von Boehmer H., Sprent J. Expression of M locus differences by B cells but not T cells. Nature. 1974 May 24;249(455):363–365. doi: 10.1038/249363a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES