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
. 1989 May;86(10):3773–3777. doi: 10.1073/pnas.86.10.3773

Model for clonal elimination in the thymus.

H Kosaka 1, M Ogata 1, I Hikita 1, S Maruo 1, S Sugihara 1, H Matsubara 1, Y Takai 1, T Hamaoka 1, H Fujiwara 1
PMCID: PMC287222  PMID: 2524833

Abstract

A thymic stromal cell clone, MRL104.8a, expresses class I as well as class II H-2k antigens after exposure to gamma-interferon. This clone also produces thymic stroma-derived T-cell growth factor (TSTGF), which is distinct from other known interleukins and is capable of promoting the growth of various antigen-specific helper T cell (Th) clones without requiring a specific antigen or interleukin 2. When the keyhole limpet hemocyanin (KLH)-specific, I-Ek-restricted Th clone 9-16 was cultured on an Ia (I-Ak and I-Ek)-expressing MRL104.8a monolayer, potent proliferation of the 9-16 cells was induced by TSTGF produced by the monolayer. In contrast, the addition of KLH resulted in lethal growth inhibition of Th clone 9-16 cells. Another Th clone that is KLH-specific but I-Ab-restricted was capable of proliferating on the Iak-expressing MRL104.8a monolayer whether or not KLH was present. More importantly, death of Th clone 9-16 cells cultured on a MRL104.8a monolayer in the presence of KLH was almost completely prevented by the addition of anti-I-Ek or anti-CD3 monoclonal antibodies, which are capable of blocking antigen recognition by the T-cell receptor. However, when Th clone 9-16 cells were cultured in the presence of KLH but on a monolayer of MRL28.8a cells, another thymic stromal clone that expresses a comparable amount of I-Ek antigen but produces a marginal amount of TSTGF, cells did not die; a lethal effect was induced by adding TSTGF. These results indicate that the TSTGF-producing and Ia-expressing thymic stromal cells induce the continuous proliferation or selective elimination of each T-cell clone, depending on whether the T-cell receptor is stimulated by the relevant antigen associated with Ia molecules expressed on the stromal cell surface.

Full text

PDF
3773

Images in this article

3774Image
on p.3774
3774Image
on p.3774
3776Image
on p.3776
3776Image
on p.3776
3776Image
on p.3776
3776Image
on p.3776

Selected References

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

  1. Asano Y., Hodes R. J. T cell regulation of b cell activation. Cloned Lyt-1+2-T suppressor cells inhibit the major histocompatibility complex-restricted interaction of T helper cells with B cells and/or accessory cells. J Exp Med. 1983 Oct 1;158(4):1178–1190. doi: 10.1084/jem.158.4.1178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beardsley T. R., Pierschbacher M., Wetzel G. D., Hays E. F. Induction of T-cell maturation by a cloned line of thymic epithelium (TEPI). Proc Natl Acad Sci U S A. 1983 Oct;80(19):6005–6009. doi: 10.1073/pnas.80.19.6005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beller D. I., Unanue E. R. IA antigens and antigen-presenting function of thymic macrophages. J Immunol. 1980 Mar;124(3):1433–1440. [PubMed] [Google Scholar]
  4. Berrih S., Arenzana-Seisdedos F., Cohen S., Devos R., Charron D., Virelizier J. L. Interferon-gamma modulates HLA class II antigen expression on cultured human thymic epithelial cells. J Immunol. 1985 Aug;135(2):1165–1171. [PubMed] [Google Scholar]
  5. 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]
  6. Farr A. G., Anderson S. K., Marrack P., Kappler J. Expression of antigen-specific, major histocompatibility complex-restricted receptors by cortical and medullary thymocytes in situ. Cell. 1985 Dec;43(2 Pt 1):543–550. doi: 10.1016/0092-8674(85)90183-7. [DOI] [PubMed] [Google Scholar]
  7. Farr A. G., Nakane P. K. Cells bearing Ia antigens in the murine thymus. An ultrastructural study. Am J Pathol. 1983 Apr;111(1):88–97. [PMC free article] [PubMed] [Google Scholar]
  8. Glimcher L. H., Kruisbeek A. M., Paul W. E., Green I. Functional activity of a transformed thymic epithelial cell line. Scand J Immunol. 1983 Jan;17(1):1–11. doi: 10.1111/j.1365-3083.1983.tb00759.x. [DOI] [PubMed] [Google Scholar]
  9. Haynes B. F. The role of the thymic microenvironment in promotion of early stages of human T cell maturation. Clin Res. 1986 Sep;34(3):422–431. [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Kingston R., Jenkinson E. J., Owen J. J. A single stem cell can recolonize an embryonic thymus, producing phenotypically distinct T-cell populations. 1985 Oct 31-Nov 6Nature. 317(6040):811–813. doi: 10.1038/317811a0. [DOI] [PubMed] [Google Scholar]
  13. 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]
  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. Lo D., Sprent J. Identity of cells that imprint H-2-restricted T-cell specificity in the thymus. Nature. 1986 Feb 20;319(6055):672–675. doi: 10.1038/319672a0. [DOI] [PubMed] [Google Scholar]
  16. Longo D. L., Kruisbeek A. M., Davis M. L., Matis L. A. Bone marrow-derived thymic antigen-presenting cells determine self-recognition of Ia-restricted T lymphocytes. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5900–5904. doi: 10.1073/pnas.82.17.5900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Longo D. L., Schwartz R. H. T-cell specificity for H-2 and Ir gene phenotype correlates with the phenotype of thymic antigen-presenting cells. Nature. 1980 Sep 4;287(5777):44–46. doi: 10.1038/287044a0. [DOI] [PubMed] [Google Scholar]
  18. Marrack P., Kappler J. The T cell receptor. Science. 1987 Nov 20;238(4830):1073–1079. doi: 10.1126/science.3317824. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Matzinger P., Zamoyska R., Waldmann H. Self tolerance is H-2-restricted. Nature. 1984 Apr 19;308(5961):738–741. doi: 10.1038/308738a0. [DOI] [PubMed] [Google Scholar]
  21. Mizushima Y., Saitoh M., Ogata M., Kosaka H., Tatsumi Y., Kiyotaki C., Hamaoka T., Fujiwara H. Thymic stroma-derived T cell growth factor (TSTGF). IV. Capacity of TSTGF to promote the growth of L3T4- Lyt-2- thymocytes by synergy with phorbol myristate acetate or various IL. J Immunol. 1989 Feb 15;142(4):1195–1202. [PubMed] [Google Scholar]
  22. Ogata M., Matsubara H., Takai Y., Kosaka H., Katagiri T., Sano H., Ishimura K., Fujita H., Hamaoka T., Fujiwara H. Capacities of a newly established thymic stromal cell clone to express Ia antigens and to produce interleukin-6, colony-stimulating factor, and thymic stroma-derived T-cell growth factor. J Leukoc Biol. 1989 Jan;45(1):69–78. doi: 10.1002/jlb.45.1.69. [DOI] [PubMed] [Google Scholar]
  23. Ogata M., Sato S., Sano H., Hamaoka T., Doi H., Nakanishi K., Asano Y., Itoh T., Fujiwara H. Thymic stroma-derived T cell growth factor (TSTGF). I. Functional distinction of TSTGF from interleukins 2 and 4 and its preferential growth-promoting effect on helper T cell clones. J Immunol. 1987 Oct 15;139(8):2675–2682. [PubMed] [Google Scholar]
  24. Ogata M., Shimizu J., Tsuchida T., Takai Y., Fujiwara H., Hamaoka T. Non-H-2-linked genetic regulation of cytotoxic responses to hapten-modified syngeneic cells. I. Non-H-2-linked Ir gene defect expressed on T cells is not predetermined at the stage of bone marrow cells. J Immunol. 1986 Feb 15;136(4):1178–1185. [PubMed] [Google Scholar]
  25. 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]
  26. Ozato K., Mayer N., Sachs D. H. Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. J Immunol. 1980 Feb;124(2):533–540. [PubMed] [Google Scholar]
  27. Ron Y., Lo D., Sprent J. T cell specificity in twice-irradiated F1----parent bone marrow chimeras: failure to detect a role for immigrant marrow-derived cells in imprinting intrathymic H-2 restriction. J Immunol. 1986 Sep 15;137(6):1764–1771. [PubMed] [Google Scholar]
  28. Rothenberg E., Lugo J. P. Differentiation and cell division in the mammalian thymus. Dev Biol. 1985 Nov;112(1):1–17. doi: 10.1016/0012-1606(85)90114-9. [DOI] [PubMed] [Google Scholar]
  29. Sato S., Ogata M., Sano H., Mizushima Y., Muramatsu M., Doi H., Itoh T., Hamaoka T., Fujiwara H. Thymic stroma-derived T-cell growth factor (TSTGF): II. Biochemical and functional characterization. J Leukoc Biol. 1988 Sep;44(3):149–157. doi: 10.1002/jlb.44.3.149. [DOI] [PubMed] [Google Scholar]
  30. Scollay R., Bartlett P., Shortman K. T cell development in the adult murine thymus: changes in the expression of the surface antigens Ly2, L3T4 and B2A2 during development from early precursor cells to emigrants. Immunol Rev. 1984 Dec;82:79–103. doi: 10.1111/j.1600-065x.1984.tb01118.x. [DOI] [PubMed] [Google Scholar]
  31. 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]
  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. Sprent J., Webb S. R. Function and specificity of T cell subsets in the mouse. Adv Immunol. 1987;41:39–133. doi: 10.1016/s0065-2776(08)60030-9. [DOI] [PubMed] [Google Scholar]
  34. Stutman O. Intrathymic and extrathymic T cell maturation. Immunol Rev. 1978;42:138–184. doi: 10.1111/j.1600-065x.1978.tb00261.x. [DOI] [PubMed] [Google Scholar]
  35. Sun T. T., Bonitz P., Burns W. H. Cell culture of mammalian thymic epithelial cells: growth, structural, and antigenic properties. Cell Immunol. 1984 Jan;83(1):1–13. doi: 10.1016/0008-8749(84)90219-3. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Widera G., Burkly L. C., Pinkert C. A., Böttger E. C., Cowing C., Palmiter R. D., Brinster R. L., Flavell R. A. Transgenic mice selectively lacking MHC class II (I-E) antigen expression on B cells: an in vivo approach to investigate Ia gene function. Cell. 1987 Oct 23;51(2):175–187. doi: 10.1016/0092-8674(87)90145-0. [DOI] [PubMed] [Google Scholar]
  38. Zinkernagel R. M. Selection of restriction specificities of virus-specific cytotoxic T cells in the thymus: no evidence for a crucial role of antigen-presenting cells. J Exp Med. 1982 Dec 1;156(6):1842–1847. doi: 10.1084/jem.156.6.1842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Zinkernagel R. M. Thymus and lymphohemopoietic cells: their role in T cell maturation in selection of T cells' H-2-restriction-specificity and in H-2 linked Ir gene control. Immunol Rev. 1978;42:224–270. doi: 10.1111/j.1600-065x.1978.tb00264.x. [DOI] [PubMed] [Google Scholar]
  40. von Boehmer H., Hafen K. Minor but not major histocompatibility antigens of thymus epithelium tolerize precursors of cytolytic T cells. Nature. 1986 Apr 17;320(6063):626–628. doi: 10.1038/320626a0. [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