Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 May 1;177(5):1429–1437. doi: 10.1084/jem.177.5.1429

Selective enrichment of major histocompatibility complex class II- specific autoreactive T cells in the thymic Thy0 subset [published erratum appears in J Exp Med 1993 Aug 1;178(2):following 763]

PMCID: PMC2191007  PMID: 8097523

Abstract

We show here a unique enrichment of autoreactive T cells in the CD4+ mouse thymic subset, Thy0. A single- and 10-cell AMLR (autologous mixed leukocyte reaction) assay demonstrates that more than 30% (one cell per well) and almost all (10 cells per well) Thy0 cultures from normal mice exhibit reactivity specific to autologous cells, resulting in induction of interleukin 3 secretion. In contrast, no other mature thymic or splenic CD4+ T cell subsets showed such a high frequency. The majority of this AMLR reactivity in the Thy0 subset is accounted for by reactivity with self-major histocompatibility complex class II. Furthermore, antigenic selection in generating Thy0 subset is suggested by studies with T cell hybrids from a T cell receptor (TCR) V beta transgenic mouse line, 2B4 beta EH. TCR V-gene analysis of T cell hybrids revealed that those from Thy0, half of which responded to self- class II, consisted predominantly of cells that expressed endogenous TCR V beta s alone (without the transgene), unlike hybrids generated from peripheral naive T cells. Thus, we suggest that the presence of Thy0 results from selective stimulation of cells expressing TCR with sufficient affinity for autoantigens in the thymic CD4+ T cell repertoire.

Full Text

The Full Text of this article is available as a PDF (917.3 KB).

Selected References

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

  1. Benoist C., Mathis D. Positive selection of the T cell repertoire: where and when does it occur? Cell. 1989 Sep 22;58(6):1027–1033. doi: 10.1016/0092-8674(89)90501-1. [DOI] [PubMed] [Google Scholar]
  2. Berg L. J., Pullen A. M., Fazekas de St Groth B., Mathis D., Benoist C., Davis M. M. Antigen/MHC-specific T cells are preferentially exported from the thymus in the presence of their MHC ligand. Cell. 1989 Sep 22;58(6):1035–1046. doi: 10.1016/0092-8674(89)90502-3. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Casanova J. L., Romero P., Widmann C., Kourilsky P., Maryanski J. L. T cell receptor genes in a series of class I major histocompatibility complex-restricted cytotoxic T lymphocyte clones specific for a Plasmodium berghei nonapeptide: implications for T cell allelic exclusion and antigen-specific repertoire. J Exp Med. 1991 Dec 1;174(6):1371–1383. doi: 10.1084/jem.174.6.1371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cerottini J. C., MacDonald H. R. The cellular basis of T-cell memory. Annu Rev Immunol. 1989;7:77–89. doi: 10.1146/annurev.iy.07.040189.000453. [DOI] [PubMed] [Google Scholar]
  6. Crispe I. N., Bevan M. J. Expression and functional significance of the J11d marker on mouse thymocytes. J Immunol. 1987 Apr 1;138(7):2013–2018. [PubMed] [Google Scholar]
  7. Faherty D. A., Johnson D. R., Zauderer M. Origin and specificity of autoreactive T cells in antigen-induced populations. J Exp Med. 1985 Jun 1;161(6):1293–1301. doi: 10.1084/jem.161.6.1293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Finnegan A., Needleman B. W., Hodes R. J. Function of autoreactive T cells in immune responses. Immunol Rev. 1990 Aug;116:15–31. doi: 10.1111/j.1600-065x.1990.tb00802.x. [DOI] [PubMed] [Google Scholar]
  9. Glimcher L. H., Longo D. L., Green I., Schwartz R. H. Murine syngeneic mixed lymphocyte response. I. Target antigens are self Ia molecules. J Exp Med. 1981 Nov 1;154(5):1652–1670. doi: 10.1084/jem.154.5.1652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Glimcher L. H., Shevach E. M. Production of autoreactive I region-restricted T cell hybridomas. J Exp Med. 1982 Aug 1;156(2):640–645. doi: 10.1084/jem.156.2.640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Haberman A. M., Moller C., McCreedy D., Gerhard W. U. A large degree of functional diversity exists among helper T cells specific for the same antigenic site of influenza hemagglutinin. J Immunol. 1990 Nov 1;145(9):3087–3094. [PubMed] [Google Scholar]
  12. Hayakawa K., Hardy R. R. Murine CD4+ T cell subsets defined. J Exp Med. 1988 Nov 1;168(5):1825–1838. doi: 10.1084/jem.168.5.1825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hayakawa K., Hardy R. R. Murine CD4+ T-cell subsets. Immunol Rev. 1991 Oct;123:145–168. doi: 10.1111/j.1600-065x.1991.tb00609.x. [DOI] [PubMed] [Google Scholar]
  14. Hayakawa K., Lin B. T., Hardy R. R. Murine CD4+ T-cell subsets generated by antigen-independent and dependent mechanisms. Chem Immunol. 1992;54:103–116. [PubMed] [Google Scholar]
  15. Hayakawa K., Lin B. T., Hardy R. R. Murine thymic CD4+ T cell subsets: a subset (Thy0) that secretes diverse cytokines and overexpresses the V beta 8 T cell receptor gene family. J Exp Med. 1992 Jul 1;176(1):269–274. doi: 10.1084/jem.176.1.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Kaye J., Hsu M. L., Sauron M. E., Jameson S. C., Gascoigne N. R., Hedrick S. M. Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor. Nature. 1989 Oct 26;341(6244):746–749. doi: 10.1038/341746a0. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Letourneur F., Malissen B. Derivation of a T cell hybridoma variant deprived of functional T cell receptor alpha and beta chain transcripts reveals a nonfunctional alpha-mRNA of BW5147 origin. Eur J Immunol. 1989 Dec;19(12):2269–2274. doi: 10.1002/eji.1830191214. [DOI] [PubMed] [Google Scholar]
  20. Lorenz R. G., Allen P. M. Direct evidence for functional self-protein/Ia-molecule complexes in vivo. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5220–5223. doi: 10.1073/pnas.85.14.5220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Malissen M., Trucy J., Jouvin-Marche E., Cazenave P. A., Scollay R., Malissen B. Regulation of TCR alpha and beta gene allelic exclusion during T-cell development. Immunol Today. 1992 Aug;13(8):315–322. doi: 10.1016/0167-5699(92)90044-8. [DOI] [PubMed] [Google Scholar]
  22. Matsui K., Boniface J. J., Reay P. A., Schild H., Fazekas de St Groth B., Davis M. M. Low affinity interaction of peptide-MHC complexes with T cell receptors. Science. 1991 Dec 20;254(5039):1788–1791. doi: 10.1126/science.1763329. [DOI] [PubMed] [Google Scholar]
  23. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  24. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Rocha B., Bandeira A. Limiting dilution analysis of interleukin-2-producing mature T cells. Interleukin 2 secretion is an exclusive property of L3T4+ lymphocytes. Scand J Immunol. 1988 Jan;27(1):47–57. doi: 10.1111/j.1365-3083.1988.tb02322.x. [DOI] [PubMed] [Google Scholar]
  27. Rudensky AYu, Preston-Hurlburt P., Hong S. C., Barlow A., Janeway C. A., Jr Sequence analysis of peptides bound to MHC class II molecules. Nature. 1991 Oct 17;353(6345):622–627. doi: 10.1038/353622a0. [DOI] [PubMed] [Google Scholar]
  28. Strober W., James S. P. Immunoregulatory function of human autoreactive T-cell lines and clones. Immunol Rev. 1990 Aug;116:117–138. doi: 10.1111/j.1600-065x.1990.tb00807.x. [DOI] [PubMed] [Google Scholar]
  29. Teh H. S., Kisielow P., Scott B., Kishi H., Uematsu Y., Blüthmann H., von Boehmer H. Thymic major histocompatibility complex antigens and the alpha beta T-cell receptor determine the CD4/CD8 phenotype of T cells. Nature. 1988 Sep 15;335(6187):229–233. doi: 10.1038/335229a0. [DOI] [PubMed] [Google Scholar]
  30. Weksler M. E., Moody C. E., Jr, Kozak R. W. The autologous mixed-lymphocyte reaction. Adv Immunol. 1981;31:271–312. doi: 10.1016/s0065-2776(08)60923-2. [DOI] [PubMed] [Google Scholar]
  31. White J., Blackman M., Bill J., Kappler J., Marrack P., Gold D. P., Born W. Two better cell lines for making hybridomas expressing specific T cell receptors. J Immunol. 1989 Sep 15;143(6):1822–1825. [PubMed] [Google Scholar]
  32. Wilson A., Day L. M., Scollay R., Shortman K. Subpopulations of mature murine thymocytes: properties of CD4-CD8+ and CD4+CD8- thymocytes lacking the heat-stable antigen. Cell Immunol. 1988 Dec;117(2):312–326. doi: 10.1016/0008-8749(88)90121-9. [DOI] [PubMed] [Google Scholar]
  33. Winoto A., Urban J. L., Lan N. C., Goverman J., Hood L., Hansburg D. Predominant use of a V alpha gene segment in mouse T-cell receptors for cytochrome c. Nature. 1986 Dec 18;324(6098):679–682. doi: 10.1038/324679a0. [DOI] [PubMed] [Google Scholar]
  34. Zauderer M. Origin and significance of autoreactive T cells. Adv Immunol. 1989;45:417–437. doi: 10.1016/s0065-2776(08)60698-7. [DOI] [PubMed] [Google Scholar]
  35. Zinkernagel R. M., Callahan G. N., Althage A., Cooper S., Klein P. A., Klein J. On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition? J Exp Med. 1978 Mar 1;147(3):882–896. doi: 10.1084/jem.147.3.882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. van Ewijk W. T-cell differentiation is influenced by thymic microenvironments. Annu Rev Immunol. 1991;9:591–615. doi: 10.1146/annurev.iy.09.040191.003111. [DOI] [PubMed] [Google Scholar]

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

RESOURCES