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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
. 1992 Jun 15;89(12):5336–5340. doi: 10.1073/pnas.89.12.5336

Selection of intraepithelial lymphocytes with CD8 alpha/alpha co-receptors by self-antigen in the murine gut.

B Rocha 1, H von Boehmer 1, D Guy-Grand 1
PMCID: PMC49286  PMID: 1608941

Abstract

We have studied T-cell receptor (TCR) and alpha/alpha CD8 expression in thymus-independent intraepithelial lymphocytes (TI IELs) from the gut of mice bearing transgenic (TG) TCR alpha beta specific for the male antigen, presented by H-2Db class I major histocompatibility complex (MHC) molecules. In contrast to TCR+ alpha beta cells differentiating in the thymus (from CD4+CD8+ precursors to CD4+CD8- or CD4-CD8+ progeny), TI IELs are not deleted by self-antigens, nor are they positively selected in the absence of the specific peptide. On the contrary, recognition of the antigen in the context of self-MHC is required for selection and granular differentiation of CD8+ TI IELs. Our results also show that, in contrast to the thymus, expression of the beta TG does not block expression of endogenous TCR gamma delta genes in TI IELs. The size of this gut IEL subpopulation and its difference in mechanisms of repertoire selection demonstrate the existence of a major extrathymic pathway of T-cell differentiation, the role of which remains to be elucidated.

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Selected References

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

  1. Abo T., Ohteki T., Seki S., Koyamada N., Yoshikai Y., Masuda T., Rikiishi H., Kumagai K. The appearance of T cells bearing self-reactive T cell receptor in the livers of mice injected with bacteria. J Exp Med. 1991 Aug 1;174(2):417–424. doi: 10.1084/jem.174.2.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bandeira A., Itohara S., Bonneville M., Burlen-Defranoux O., Mota-Santos T., Coutinho A., Tonegawa S. Extrathymic origin of intestinal intraepithelial lymphocytes bearing T-cell antigen receptor gamma delta. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):43–47. doi: 10.1073/pnas.88.1.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bleicher P. A., Balk S. P., Hagen S. J., Blumberg R. S., Flotte T. J., Terhorst C. Expression of murine CD1 on gastrointestinal epithelium. Science. 1990 Nov 2;250(4981):679–682. doi: 10.1126/science.1700477. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Carding S. R., Kyes S., Jenkinson E. J., Kingston R., Bottomly K., Owen J. J., Hayday A. C. Developmentally regulated fetal thymic and extrathymic T-cell receptor gamma delta gene expression. Genes Dev. 1990 Aug;4(8):1304–1315. doi: 10.1101/gad.4.8.1304. [DOI] [PubMed] [Google Scholar]
  6. Croitoru K., Stead R. H., Bienenstock J., Fulop G., Harnish D. G., Shultz L. D., Jeffery P. K., Ernst P. B. Presence of intestinal intraepithelial lymphocytes in mice with severe combined immunodeficiency disease. Eur J Immunol. 1990 Mar;20(3):645–651. doi: 10.1002/eji.1830200327. [DOI] [PubMed] [Google Scholar]
  7. Cron R. Q., Gajewski T. F., Sharrow S. O., Fitch F. W., Matis L. A., Bluestone J. A. Phenotypic and functional analysis of murine CD3+,CD4-,CD8- TCR-gamma delta-expressing peripheral T cells. J Immunol. 1989 Jun 1;142(11):3754–3762. [PubMed] [Google Scholar]
  8. Dialynas D. P., Quan Z. S., Wall K. A., Pierres A., Quintáns J., Loken M. R., Pierres M., Fitch F. W. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J Immunol. 1983 Nov;131(5):2445–2451. [PubMed] [Google Scholar]
  9. Fry A. M., Jones L. A., Kruisbeek A. M., Matis L. A. Thymic requirement for clonal deletion during T cell development. Science. 1989 Nov 24;246(4933):1044–1046. doi: 10.1126/science.2511630. [DOI] [PubMed] [Google Scholar]
  10. Goodman T., Lefrancois L. Intraepithelial lymphocytes. Anatomical site, not T cell receptor form, dictates phenotype and function. J Exp Med. 1989 Nov 1;170(5):1569–1581. doi: 10.1084/jem.170.5.1569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Guy-Grand D., Cerf-Bensussan N., Malissen B., Malassis-Seris M., Briottet C., Vassalli P. Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation. J Exp Med. 1991 Feb 1;173(2):471–481. doi: 10.1084/jem.173.2.471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Guy-Grand D., Griscelli C., Vassalli P. The mouse gut T lymphocyte, a novel type of T cell. Nature, origin, and traffic in mice in normal and graft-versus-host conditions. J Exp Med. 1978 Dec 1;148(6):1661–1677. doi: 10.1084/jem.148.6.1661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Guy-Grand D., Malassis-Seris M., Briottet C., Vassalli P. Cytotoxic differentiation of mouse gut thymodependent and independent intraepithelial T lymphocytes is induced locally. Correlation between functional assays, presence of perforin and granzyme transcripts, and cytoplasmic granules. J Exp Med. 1991 Jun 1;173(6):1549–1552. doi: 10.1084/jem.173.6.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Guy-Grand D., Vanden Broecke C., Briottet C., Malassis-Seris M., Selz F., Vassalli P. Different expression of the recombination activity gene RAG-1 in various populations of thymocytes, peripheral T cells and gut thymus-independent intraepithelial lymphocytes suggests two pathways of T cell receptor rearrangement. Eur J Immunol. 1992 Feb;22(2):505–510. doi: 10.1002/eji.1830220232. [DOI] [PubMed] [Google Scholar]
  15. Guy-Grand D., Vassalli P. Gut injury in mouse graft-versus-host reaction. Study of its occurrence and mechanisms. J Clin Invest. 1986 May;77(5):1584–1595. doi: 10.1172/JCI112474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hershberg R., Eghtesady P., Sydora B., Brorson K., Cheroutre H., Modlin R., Kronenberg M. Expression of the thymus leukemia antigen in mouse intestinal epithelium. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9727–9731. doi: 10.1073/pnas.87.24.9727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Huesmann M., Scott B., Kisielow P., von Boehmer H. Kinetics and efficacy of positive selection in the thymus of normal and T cell receptor transgenic mice. Cell. 1991 Aug 9;66(3):533–540. doi: 10.1016/0092-8674(81)90016-7. [DOI] [PubMed] [Google Scholar]
  18. Ishida I., Verbeek S., Bonneville M., Itohara S., Berns A., Tonegawa S. T-cell receptor gamma delta and gamma transgenic mice suggest a role of a gamma gene silencer in the generation of alpha beta T cells. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3067–3071. doi: 10.1073/pnas.87.8.3067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. 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]
  21. 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]
  22. 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]
  23. MacDonald H. R., Lees R. K., Bron C., Sordat B., Miescher G. T cell antigen receptor expression in athymic (nu/nu) mice. Evidence for an oligoclonal beta chain repertoire. J Exp Med. 1987 Jul 1;166(1):195–209. doi: 10.1084/jem.166.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. MacDonald H. R., Schneider R., Lees R. K., Howe R. C., Acha-Orbea H., Festenstein H., Zinkernagel R. M., Hengartner H. T-cell receptor V beta use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature. 1988 Mar 3;332(6159):40–45. doi: 10.1038/332040a0. [DOI] [PubMed] [Google Scholar]
  25. Papiernik M., Pontoux C. In vivo and in vitro repertoire of CD3+CD4-CD8- thymocytes. Int Immunol. 1990;2(5):407–412. doi: 10.1093/intimm/2.5.407. [DOI] [PubMed] [Google Scholar]
  26. Pereira P., Zijlstra M., McMaster J., Loring J. M., Jaenisch R., Tonegawa S. Blockade of transgenic gamma delta T cell development in beta 2-microglobulin deficient mice. EMBO J. 1992 Jan;11(1):25–31. doi: 10.1002/j.1460-2075.1992.tb05023.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Raulet D. H., Spencer D. M., Hsiang Y. H., Goldman J. P., Bix M., Liao N. S., Zijstra M., Jaenisch R., Correa I. Control of gamma delta T-cell development. Immunol Rev. 1991 Apr;120:185–204. doi: 10.1111/j.1600-065x.1991.tb00592.x. [DOI] [PubMed] [Google Scholar]
  28. Rocha B. Characterization of V beta-bearing cells in athymic (nu/nu) mice suggests an extrathymic pathway for T cell differentiation. Eur J Immunol. 1990 Apr;20(4):919–925. doi: 10.1002/eji.1830200430. [DOI] [PubMed] [Google Scholar]
  29. Rocha B., Vassalli P., Guy-Grand D. The V beta repertoire of mouse gut homodimeric alpha CD8+ intraepithelial T cell receptor alpha/beta + lymphocytes reveals a major extrathymic pathway of T cell differentiation. J Exp Med. 1991 Feb 1;173(2):483–486. doi: 10.1084/jem.173.2.483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sim G. K., Augustin A. Extrathymic positive selection of gamma delta T cells. V gamma 4J gamma 1 rearrangements with "GxYS" junctions. J Immunol. 1991 Apr 1;146(7):2439–2445. [PubMed] [Google Scholar]
  31. Teh H. S., Kishi H., Scott B., Von Boehmer H. Deletion of autospecific T cells in T cell receptor (TCR) transgenic mice spares cells with normal TCR levels and low levels of CD8 molecules. J Exp Med. 1989 Mar 1;169(3):795–806. doi: 10.1084/jem.169.3.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. Winoto A., Baltimore D. Alpha beta lineage-specific expression of the alpha T cell receptor gene by nearby silencers. Cell. 1989 Nov 17;59(4):649–655. doi: 10.1016/0092-8674(89)90010-x. [DOI] [PubMed] [Google Scholar]
  34. Wu M., van Kaer L., Itohara S., Tonegawa S. Highly restricted expression of the thymus leukemia antigens on intestinal epithelial cells. J Exp Med. 1991 Jul 1;174(1):213–218. doi: 10.1084/jem.174.1.213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. von Boehmer H., Kirberg J., Rocha B. An unusual lineage of alpha/beta T cells that contains autoreactive cells. J Exp Med. 1991 Nov 1;174(5):1001–1008. doi: 10.1084/jem.174.5.1001. [DOI] [PMC free article] [PubMed] [Google Scholar]

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