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. 1991 Feb 1;173(2):471–481. doi: 10.1084/jem.173.2.471

Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation

PMCID: PMC2118788  PMID: 1824857

Abstract

Mouse gut intraepithelial lymphocytes (IEL) consist mainly (90%) of two populations of CD8+ T cells. One bears heterodimeric alpha/beta CD8 chains (Lyt-2+, Lyt-3+), a T cell receptor (TCR) made of alpha/beta chains, and is Thy-1+; it represents the progeny of T blasts elicited in Peyer's patches by antigenic stimulation. The other bears homodimeric alpha/alpha CD8+ chains, contains no beta chain mRNA, and is mostly Thy-1- and TCR-gamma/delta + or -alpha/beta +; it is thymo- independent and does not require antigenic stimulation, as shown by its presence: (a) in nude and scid mice; (b) in irradiated and thymectomized mice repopulated by T-depleted bone marrow cells bearing an identifiable marker; (c) in thymectomized mice treated by injections of monoclonal anti-CD8 antibody, which lead to total depletion of peripheral CD8+ T lymphocytes; and (d) in germ-free mice and in suckling mice. In young nude mice, alpha/alpha CD8 chains, CD3-TCR complexes, and TCR mRNAs (first gamma/delta) are found on IEL, while they are not detectable on or in peripheral or circulating lymphocytes or bone marrow cells. IEL, in contrast to mature T cells, contain mRNA for the RAG protein, which is required for the rearrangement of TCR and Ig genes. We propose that the gut epithelium (an endoderm derivative, as the thymic epithelium) has an inductive property, attracting progenitors of bone marrow origin, and triggering their TCR rearrangement and alpha/alpha CD8 chains expression, thus giving rise to a T cell population that appears to belong to the same lineage as gamma/delta thymocytes and to recognize an antigenic repertoire different from that of alpha/beta CD8+ IEL.

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Selected References

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  1. Asarnow D. M., Kuziel W. A., Bonyhadi M., Tigelaar R. E., Tucker P. W., Allison J. P. Limited diversity of gamma delta antigen receptor genes of Thy-1+ dendritic epidermal cells. Cell. 1988 Dec 2;55(5):837–847. doi: 10.1016/0092-8674(88)90139-0. [DOI] [PubMed] [Google Scholar]
  2. Benveniste P., Chadwick B. S., Miller R. G., Reimann J. Characterization of cells with T cell markers in athymic nude bone marrow and of their in vitro-derived clonal progeny. Comparison with euthymic bone marrow. J Immunol. 1990 Jan 15;144(2):411–419. [PubMed] [Google Scholar]
  3. Bertho J. M., Mossalayi M. D., Dalloul A. H., Mouterde G., Debre P. Isolation of an early T-cell precursor (CFU-TL) from human bone marrow. Blood. 1990 Mar 1;75(5):1064–1068. [PubMed] [Google Scholar]
  4. Blanc D., Bron C., Gabert J., Letourneur F., MacDonald H. R., Malissen B. Gene transfer of the Ly-3 chain gene of the mouse CD8 molecular complex: co-transfer with the Ly-2 polypeptide gene results in detectable cell surface expression of the Ly-3 antigenic determinants. Eur J Immunol. 1988 Apr;18(4):613–619. doi: 10.1002/eji.1830180419. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Bonneville M., Itohara S., Krecko E. G., Mombaerts P., Ishida I., Katsuki M., Berns A., Farr A. G., Janeway C. A., Jr, Tonegawa S. Transgenic mice demonstrate that epithelial homing of gamma/delta T cells is determined by cell lineages independent of T cell receptor specificity. J Exp Med. 1990 Apr 1;171(4):1015–1026. doi: 10.1084/jem.171.4.1015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bonneville M., Janeway C. A., Jr, Ito K., Haser W., Ishida I., Nakanishi N., Tonegawa S. Intestinal intraepithelial lymphocytes are a distinct set of gamma delta T cells. Nature. 1988 Dec 1;336(6198):479–481. doi: 10.1038/336479a0. [DOI] [PubMed] [Google Scholar]
  8. Cerf-Bensussan N., Guy-Grand D., Lisowska-Grospierre B., Griscelli C., Bhan A. K. A monoclonal antibody specific for rat intestinal lymphocytes. J Immunol. 1986 Jan;136(1):76–82. [PubMed] [Google Scholar]
  9. Cerf-Bensussan N., Jarry A., Brousse N., Lisowska-Grospierre B., Guy-Grand D., Griscelli C. A monoclonal antibody (HML-1) defining a novel membrane molecule present on human intestinal lymphocytes. Eur J Immunol. 1987 Sep;17(9):1279–1285. doi: 10.1002/eji.1830170910. [DOI] [PubMed] [Google Scholar]
  10. Chien Y. H., Iwashima M., Kaplan K. B., Elliott J. F., Davis M. M. A new T-cell receptor gene located within the alpha locus and expressed early in T-cell differentiation. 1987 Jun 25-Jul 1Nature. 327(6124):677–682. doi: 10.1038/327677a0. [DOI] [PubMed] [Google Scholar]
  11. Cobbold S. P., Jayasuriya A., Nash A., Prospero T. D., Waldmann H. Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature. 1984 Dec 6;312(5994):548–551. doi: 10.1038/312548a0. [DOI] [PubMed] [Google Scholar]
  12. Collart M. A., Belin D., Vassalli J. D., de Kossodo S., Vassalli P. Gamma interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors. J Exp Med. 1986 Dec 1;164(6):2113–2118. doi: 10.1084/jem.164.6.2113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. De Geus B., Van den Enden M., Coolen C., Nagelkerken L., Van der Heijden P., Rozing J. Phenotype of intraepithelial lymphocytes in euthymic and athymic mice: implications for differentiation of cells bearing a CD3-associated gamma delta T cell receptor. Eur J Immunol. 1990 Feb;20(2):291–298. doi: 10.1002/eji.1830200210. [DOI] [PubMed] [Google Scholar]
  16. Deugnier M. A., Imhof B. A., Bauvois B., Dunon D., Denoyelle M., Thiery J. P. Characterization of rat T cell precursors sorted by chemotactic migration toward thymotaxin. Cell. 1989 Mar 24;56(6):1073–1083. doi: 10.1016/0092-8674(89)90640-5. [DOI] [PubMed] [Google Scholar]
  17. Goff L. K., Larsson L., Fisher A. G. Expression of high molecular weight isoforms of CD45 by mouse thymic progenitor cells. Eur J Immunol. 1990 Mar;20(3):665–671. doi: 10.1002/eji.1830200330. [DOI] [PubMed] [Google Scholar]
  18. Gresser I., Guy-Grand D., Maury C., Maunoury M. T. Interferon induces peripheral lymphadenopathy in mice. J Immunol. 1981 Oct;127(4):1569–1575. [PubMed] [Google Scholar]
  19. Guy-Grand D., Griscelli C., Vassalli P. The gut-associated lymphoid system: nature and properties of the large dividing cells. Eur J Immunol. 1974 Jun;4(6):435–443. doi: 10.1002/eji.1830040610. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. Habu S., Okumura K. Cell surface antigen marking the stages of murine T cell ontogeny and its functional subsets. Immunol Rev. 1984 Dec;82:117–139. doi: 10.1111/j.1600-065x.1984.tb01120.x. [DOI] [PubMed] [Google Scholar]
  23. Haynes B. F., Martin M. E., Kay H. H., Kurtzberg J. Early events in human T cell ontogeny. Phenotypic characterization and immunohistologic localization of T cell precursors in early human fetal tissues. J Exp Med. 1988 Sep 1;168(3):1061–1080. doi: 10.1084/jem.168.3.1061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hurwitz J. L., Samaridis J., Pelkonen J. Progression of rearrangements at T cell receptor beta and gamma gene loci during athymic differentiation of bone marrow cells in vitro. Cell. 1988 Mar 25;52(6):821–829. doi: 10.1016/0092-8674(88)90424-2. [DOI] [PubMed] [Google Scholar]
  25. Ito K., Bonneville M., Takagaki Y., Nakanishi N., Kanagawa O., Krecko E. G., Tonegawa S. Different gamma delta T-cell receptors are expressed on thymocytes at different stages of development. Proc Natl Acad Sci U S A. 1989 Jan;86(2):631–635. doi: 10.1073/pnas.86.2.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ito K., Van Kaer L., Bonneville M., Hsu S., Murphy D. B., Tonegawa S. Recognition of the product of a novel MHC TL region gene (27b) by a mouse gamma delta T cell receptor. Cell. 1990 Aug 10;62(3):549–561. doi: 10.1016/0092-8674(90)90019-b. [DOI] [PubMed] [Google Scholar]
  27. Itohara S., Farr A. G., Lafaille J. J., Bonneville M., Takagaki Y., Haas W., Tonegawa S. Homing of a gamma delta thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature. 1990 Feb 22;343(6260):754–757. doi: 10.1038/343754a0. [DOI] [PubMed] [Google Scholar]
  28. Iwamoto A., Rupp F., Ohashi P. S., Walker C. L., Pircher H., Joho R., Hengartner H., Mak T. W. T cell-specific gamma genes in C57BL/10 mice. Sequence and expression of new constant and variable region genes. J Exp Med. 1986 May 1;163(5):1203–1212. doi: 10.1084/jem.163.5.1203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jarry A., Cerf-Bensussan N., Brousse N., Selz F., Guy-Grand D. Subsets of CD3+ (T cell receptor alpha/beta or gamma/delta) and CD3- lymphocytes isolated from normal human gut epithelium display phenotypical features different from their counterparts in peripheral blood. Eur J Immunol. 1990 May;20(5):1097–1103. doi: 10.1002/eji.1830200523. [DOI] [PubMed] [Google Scholar]
  30. Kilshaw P. J., Baker K. C. A unique surface antigen on intraepithelial lymphocytes in the mouse. Immunol Lett. 1988 Jun;18(2):149–154. doi: 10.1016/0165-2478(88)90056-9. [DOI] [PubMed] [Google Scholar]
  31. Krissansen G. W., Owen M. J., Fink P. J., Crumpton M. J. Molecular cloning of the cDNA encoding the T3 gamma subunit of the mouse T3/T cell antigen receptor complex. J Immunol. 1987 May 15;138(10):3513–3518. [PubMed] [Google Scholar]
  32. 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]
  33. Lafaille J. J., DeCloux A., Bonneville M., Takagaki Y., Tonegawa S. Junctional sequences of T cell receptor gamma delta genes: implications for gamma delta T cell lineages and for a novel intermediate of V-(D)-J joining. Cell. 1989 Dec 1;59(5):859–870. doi: 10.1016/0092-8674(89)90609-0. [DOI] [PubMed] [Google Scholar]
  34. Ledbetter J. A., Seaman W. E., Tsu T. T., Herzenberg L. A. Lyt-2 and lyt-3 antigens are on two different polypeptide subunits linked by disulfide bonds. Relationship of subunits to T cell cytolytic activity. J Exp Med. 1981 Jun 1;153(6):1503–1516. doi: 10.1084/jem.153.6.1503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Malissen M., Minard K., Mjolsness S., Kronenberg M., Goverman J., Hunkapiller T., Prystowsky M. B., Yoshikai Y., Fitch F., Mak T. W. Mouse T cell antigen receptor: structure and organization of constant and joining gene segments encoding the beta polypeptide. Cell. 1984 Jul;37(3):1101–1110. doi: 10.1016/0092-8674(84)90444-6. [DOI] [PubMed] [Google Scholar]
  36. Malissen M., Trucy J., Letourneur F., Rebaï N., Dunn D. E., Fitch F. W., Hood L., Malissen B. A T cell clone expresses two T cell receptor alpha genes but uses one alpha beta heterodimer for allorecognition and self MHC-restricted antigen recognition. Cell. 1988 Oct 7;55(1):49–59. doi: 10.1016/0092-8674(88)90008-6. [DOI] [PubMed] [Google Scholar]
  37. Marrack P., Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990 May 11;248(4956):705–711. doi: 10.1126/science.2185544. [DOI] [PubMed] [Google Scholar]
  38. Miescher G. C., Liao N. S., Lees R. K., MacDonald H. R., Raulet D. H. Selective expression of V delta 6 genes by B2A2- CD4- CD8- T cell receptor gamma/delta thymocytes. Eur J Immunol. 1990 Jan;20(1):41–45. doi: 10.1002/eji.1830200107. [DOI] [PubMed] [Google Scholar]
  39. Minty A. J., Alonso S., Caravatti M., Buckingham M. E. A fetal skeletal muscle actin mRNA in the mouse and its identity with cardiac actin mRNA. Cell. 1982 Aug;30(1):185–192. doi: 10.1016/0092-8674(82)90024-1. [DOI] [PubMed] [Google Scholar]
  40. Oettinger M. A., Schatz D. G., Gorka C., Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990 Jun 22;248(4962):1517–1523. doi: 10.1126/science.2360047. [DOI] [PubMed] [Google Scholar]
  41. Parrott D. M., Tait C., MacKenzie S., Mowat A. M., Davies M. D., Micklem H. S. Analysis of the effector functions of different populations of mucosal lymphocytes. Ann N Y Acad Sci. 1983 Jun 30;409:307–320. doi: 10.1111/j.1749-6632.1983.tb26879.x. [DOI] [PubMed] [Google Scholar]
  42. Pullen A. M., Wade T., Marrack P., Kappler J. W. Identification of the region of T cell receptor beta chain that interacts with the self-superantigen MIs-1a. Cell. 1990 Jun 29;61(7):1365–1374. doi: 10.1016/0092-8674(90)90700-o. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. Ryser J. E., Vassalli P. Mouse bone marrow lymphocytes and their differentiation. J Immunol. 1974 Sep;113(3):719–728. [PubMed] [Google Scholar]
  45. Schatz D. G., Oettinger M. A., Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 1989 Dec 22;59(6):1035–1048. doi: 10.1016/0092-8674(89)90760-5. [DOI] [PubMed] [Google Scholar]
  46. Schieferdecker H. L., Ullrich R., Weiss-Breckwoldt A. N., Schwarting R., Stein H., Riecken E. O., Zeitz M. The HML-1 antigen of intestinal lymphocytes is an activation antigen. J Immunol. 1990 Apr 1;144(7):2541–2549. [PubMed] [Google Scholar]
  47. Schuler W., Weiler I. J., Schuler A., Phillips R. A., Rosenberg N., Mak T. W., Kearney J. F., Perry R. P., Bosma M. J. Rearrangement of antigen receptor genes is defective in mice with severe combined immune deficiency. Cell. 1986 Sep 26;46(7):963–972. doi: 10.1016/0092-8674(86)90695-1. [DOI] [PubMed] [Google Scholar]
  48. Takagaki Y., DeCloux A., Bonneville M., Tonegawa S. Diversity of gamma delta T-cell receptors on murine intestinal intra-epithelial lymphocytes. Nature. 1989 Jun 29;339(6227):712–714. doi: 10.1038/339712a0. [DOI] [PubMed] [Google Scholar]
  49. Thorens B., Schulz M. F., Vassalli P. Bone marrow pre-B lymphocytes synthesize immunoglobulin mu chains of membrane type with different properties and intracellular pathways. EMBO J. 1985 Feb;4(2):361–368. doi: 10.1002/j.1460-2075.1985.tb03637.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. von Boehmer H. Developmental biology of T cells in T cell-receptor transgenic mice. Annu Rev Immunol. 1990;8:531–556. doi: 10.1146/annurev.iy.08.040190.002531. [DOI] [PubMed] [Google Scholar]

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