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. 1996 May 1;183(5):2355–2360. doi: 10.1084/jem.183.5.2355

Protection from anti-TCR/CD3-induced apoptosis in immature thymocytes by a signal through thymic shared antigen-1/stem cell antigen-2

PMCID: PMC2192583  PMID: 8642345

Abstract

During T cell development in the thymus, the expression of thymic shared antigen-1 (TSA-1)/stem cell antigen-2 (Sca-2), a glycosylphosphatidylinositol (GPI)-anchored differentiation antigen, is developmentally regulated. The expression level of TSA-1 is the highest in most immature CD4- CD8- thymocytes, high in CD4+ CD8+ thymocytes, but barely detectable in mature CD4+ CD8- or CD4- CD8- thymocytes and peripheral T cells. We have previously shown that surface TSA-1 expression in peripheral T cells is induced upon activation and that anti-TSA-1 mAb inhibits the T cell receptor (TCR) signaling pathway in activated T cells. In the present study, we have analyzed a role of TSA- 1 in thymic selection events, especially in TCR-mediated apoptosis. In in vitro experiments, anti-TSA-1 blocked anti-CD3-induced cell death of T cell hybridomas. When anti-TSA-1 was injected into newborn mice in vivo together with anti-CD3 epsilon or anti-TCR-beta, TCR/CD3-mediated apoptosis of thymocytes was almost completely blocked. The blockade of apoptosis was defined by the inhibition of, first, the decrease in total number of thymocytes; second, the decrease in percentages of CD4+ CD8+ thymocytes; and third, the induction of DNA fragmentation. However, anti-TSA-1 did not block either steroid- or radiation-induced apoptosis, indicating that a signal via TSA-1 does not inhibit a common pathway of thymocyte apoptosis. Since TCR-mediated apoptosis is pivotal in thymic ontogeny, these results suggest that TSA-1/Sca-2 is an important cell surface molecule regulating the fate of a developing T cell.

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Selected References

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  1. Antica M., Wu L., Shortman K., Scollay R. Thymic stem cells in mouse bone marrow. Blood. 1994 Jul 1;84(1):111–117. [PubMed] [Google Scholar]
  2. Ashwell J. D., Cunningham R. E., Noguchi P. D., Hernandez D. Cell growth cycle block of T cell hybridomas upon activation with antigen. J Exp Med. 1987 Jan 1;165(1):173–194. doi: 10.1084/jem.165.1.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bamezai A., Palliser D., Berezovskaya A., McGrew J., Higgins K., Lacy E., Rock K. L. Regulated expression of Ly-6A.2 is important for T cell development. J Immunol. 1995 May 1;154(9):4233–4239. [PubMed] [Google Scholar]
  4. Bamezai A., Rock K. L. Overexpressed Ly-6A.2 mediates cell-cell adhesion by binding a ligand expressed on lymphoid cells. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4294–4298. doi: 10.1073/pnas.92.10.4294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Classon B. J., Coverdale L. Mouse stem cell antigen Sca-2 is a member of the Ly-6 family of cell surface proteins. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5296–5300. doi: 10.1073/pnas.91.12.5296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Codias E. K., Rutter J. E., Fleming T. J., Malek T. R. Down-regulation of IL-2 production by activation of T cells through Ly-6A/E. J Immunol. 1990 Sep 1;145(5):1407–1414. [PubMed] [Google Scholar]
  7. Cohen J. J., Duke R. C., Fadok V. A., Sellins K. S. Apoptosis and programmed cell death in immunity. Annu Rev Immunol. 1992;10:267–293. doi: 10.1146/annurev.iy.10.040192.001411. [DOI] [PubMed] [Google Scholar]
  8. Godfrey D. I., Masciantonio M., Tucek C. L., Malin M. A., Boyd R. L., Hugo P. Thymic shared antigen-1. A novel thymocyte marker discriminating immature from mature thymocyte subsets. J Immunol. 1992 Apr 1;148(7):2006–2011. [PubMed] [Google Scholar]
  9. Godfrey D. I., Zlotnik A. Control points in early T-cell development. Immunol Today. 1993 Nov;14(11):547–553. doi: 10.1016/0167-5699(93)90186-O. [DOI] [PubMed] [Google Scholar]
  10. Gunter K. C., Malek T. R., Shevach E. M. T cell-activating properties of an anti-Thy-1 monoclonal antibody. Possible analogy to OKT3/Leu-4. J Exp Med. 1984 Mar 1;159(3):716–730. doi: 10.1084/jem.159.3.716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Kosugi A., Saitoh S., Narumiya S., Miyake K., Hamaoka T. Activation-induced expression of thymic shared antigen-1 on T lymphocytes and its inhibitory role for TCR-mediated IL-2 production. Int Immunol. 1994 Dec;6(12):1967–1976. doi: 10.1093/intimm/6.12.1967. [DOI] [PubMed] [Google Scholar]
  13. Kubo R. T., Born W., Kappler J. W., Marrack P., Pigeon M. Characterization of a monoclonal antibody which detects all murine alpha beta T cell receptors. J Immunol. 1989 Apr 15;142(8):2736–2742. [PubMed] [Google Scholar]
  14. 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]
  15. MacNeil I., Kennedy J., Godfrey D. I., Jenkins N. A., Masciantonio M., Mineo C., Gilbert D. J., Copeland N. G., Boyd R. L., Zlotnik A. Isolation of a cDNA encoding thymic shared antigen-1. A new member of the Ly6 family with a possible role in T cell development. J Immunol. 1993 Dec 15;151(12):6913–6923. [PubMed] [Google Scholar]
  16. Randle E. S., Waanders G. A., Masciantonio M., Godfrey D. I., Boyd R. L. A lymphostromal molecule, thymic shared Ag-1, regulates early thymocyte development in fetal thymus organ culture. J Immunol. 1993 Dec 1;151(11):6027–6035. [PubMed] [Google Scholar]
  17. Saitoh S., Kosugi A., Noda S., Yamamoto N., Ogata M., Minami Y., Miyake K., Hamaoka T. Modulation of TCR-mediated signaling pathway by thymic shared antigen-1 (TSA-1)/stem cell antigen-2 (Sca-2). J Immunol. 1995 Dec 15;155(12):5574–5581. [PubMed] [Google Scholar]
  18. Shi Y. F., Sahai B. M., Green D. R. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature. 1989 Jun 22;339(6226):625–626. doi: 10.1038/339625a0. [DOI] [PubMed] [Google Scholar]
  19. Spangrude G. J., Aihara Y., Weissman I. L., Klein J. The stem cell antigens Sca-1 and Sca-2 subdivide thymic and peripheral T lymphocytes into unique subsets. J Immunol. 1988 Dec 1;141(11):3697–3707. [PubMed] [Google Scholar]
  20. Wu L., Antica M., Johnson G. R., Scollay R., Shortman K. Developmental potential of the earliest precursor cells from the adult mouse thymus. J Exp Med. 1991 Dec 1;174(6):1617–1627. doi: 10.1084/jem.174.6.1617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. von Boehmer H. Thymic selection: a matter of life and death. Immunol Today. 1992 Nov;13(11):454–458. doi: 10.1016/0167-5699(92)90075-I. [DOI] [PubMed] [Google Scholar]

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