Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Aug 1;180(2):433–444. doi: 10.1084/jem.180.2.433

Heterogeneity and biased T cell receptor alpha/beta repertoire of mucosal CD8+ cells from murine large intestine: implications for functional state

PMCID: PMC2191605  PMID: 8046326

Abstract

Up to 90% of CD8+ intraepithelial lymphocytes (IEL) of the murine large intestine (LI) belong to the alpha/beta T cell lineage and consist of two subsets. One subset expresses both alpha and beta subunits of the CD8 coreceptor, and is uniformly Thy1+, CD5+, B220-, CD2+, CD28+. The CD8 alpha+beta+ LI-IEL exclude self-reacting V beta structures, and readily proliferate in vivo in response to T cell receptor-mediated stimuli. The CD8 alpha+beta- subset of TCR-alpha/beta+ LI-IEL is Thy1- /+, CD5-, B220+, CD2+/-, and CD28-. It contains cells with potentially self-reacting V beta s and is responsive in vivo to high doses of anti- TCR-alpha/beta monoclonal antibody (mAb), but not to bacterial superantigens. Both subsets are abundant in LI-IEL of old nude mice, and CD8 alpha+beta+ LI-IEL in nude mice undergo the same V beta deletions as in euthymic mice of the same background. Both subsets express the intestinal T cell-specific integrin alpha M290 beta 7, known to be a homing receptor for IEL. Unusually high proportions of CD69+ cells within both subsets indicate chronic activation. The proportions of CD69+ and alpha M290 beta 7+ cells within the CD8 alpha+beta+ subset increase with age, probably due to constant antigenic challenge. We propose that CD8 alpha+beta+ and CD8 alpha+beta- subsets of LI-IEL permanently reside in LI and represent a lineage different from spleen and lymph node CD8+ T cells. The CD8 alpha+beta+ undergoes negative selection, and is responsive to TCR-mediated stimuli. The CD8 alpha+beta- subset of LI-IEL is a subject of distinct selection mechanisms, and has low responsiveness to TCR-mediated stimuli.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. Alberola-Ila J., Places L., Lozano F., Vives J. Association of an activation inducible serine kinase activity with CD5. J Immunol. 1993 Nov 1;151(9):4423–4430. [PubMed] [Google Scholar]
  2. Beagley K. W., Fujihashi K., Black C. A., Lagoo A. S., Yamamoto M., McGhee J. R., Kiyono H. The Mycobacterium tuberculosis 71-kDa heat-shock protein induces proliferation and cytokine secretion by murine gut intraepithelial lymphocytes. Eur J Immunol. 1993 Aug;23(8):2049–2052. doi: 10.1002/eji.1830230852. [DOI] [PubMed] [Google Scholar]
  3. Beyers A. D., Spruyt L. L., Williams A. F. Molecular associations between the T-lymphocyte antigen receptor complex and the surface antigens CD2, CD4, or CD8 and CD5. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2945–2949. doi: 10.1073/pnas.89.7.2945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bill J., Kanagawa O., Woodland D. L., Palmer E. The MHC molecule I-E is necessary but not sufficient for the clonal deletion of V beta 11-bearing T cells. J Exp Med. 1989 Apr 1;169(4):1405–1419. doi: 10.1084/jem.169.4.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Budd R. C., Cerottini J. C., Horvath C., Bron C., Pedrazzini T., Howe R. C., MacDonald H. R. Distinction of virgin and memory T lymphocytes. Stable acquisition of the Pgp-1 glycoprotein concomitant with antigenic stimulation. J Immunol. 1987 May 15;138(10):3120–3129. [PubMed] [Google Scholar]
  6. Budd R. C., Russell J. Q., van Houten N., Cooper S. M., Yagita H., Wolfe J. CD2 expression correlates with proliferative capacity of alpha beta + or gamma delta + CD4-CD8- T cells in lpr mice. J Immunol. 1992 Feb 15;148(4):1055–1064. [PubMed] [Google Scholar]
  7. Camerini V., Panwala C., Kronenberg M. Regional specialization of the mucosal immune system. Intraepithelial lymphocytes of the large intestine have a different phenotype and function than those of the small intestine. J Immunol. 1993 Aug 15;151(4):1765–1776. [PubMed] [Google Scholar]
  8. Carmo A. M., Mason D. W., Beyers A. D. Physical association of the cytoplasmic domain of CD2 with the tyrosine kinases p56lck and p59fyn. Eur J Immunol. 1993 Sep;23(9):2196–2201. doi: 10.1002/eji.1830230922. [DOI] [PubMed] [Google Scholar]
  9. Correa I., Bix M., Liao N. S., Zijlstra M., Jaenisch R., Raulet D. Most gamma delta T cells develop normally in beta 2-microglobulin-deficient mice. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):653–657. doi: 10.1073/pnas.89.2.653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dillon S. B., Dalton B. J., MacDonald T. T. Lymphokine production by mitogen and antigen activated mouse intraepithelial lymphocytes. Cell Immunol. 1986 Dec;103(2):326–338. doi: 10.1016/0008-8749(86)90093-6. [DOI] [PubMed] [Google Scholar]
  11. Fujihashi K., Taguchi T., Aicher W. K., McGhee J. R., Bluestone J. A., Eldridge J. H., Kiyono H. Immunoregulatory functions for murine intraepithelial lymphocytes: gamma/delta T cell receptor-positive (TCR+) T cells abrogate oral tolerance, while alpha/beta TCR+ T cells provide B cell help. J Exp Med. 1992 Mar 1;175(3):695–707. doi: 10.1084/jem.175.3.695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Giese T., Davidson W. F. Evidence for early onset, polyclonal activation of T cell subsets in mice homozygous for lpr. J Immunol. 1992 Nov 1;149(9):3097–3106. [PubMed] [Google Scholar]
  13. 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]
  14. Goodman T., Lefrançois L. Expression of the gamma-delta T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature. 1988 Jun 30;333(6176):855–858. doi: 10.1038/333855a0. [DOI] [PubMed] [Google Scholar]
  15. Gross J. A., Callas E., Allison J. P. Identification and distribution of the costimulatory receptor CD28 in the mouse. J Immunol. 1992 Jul 15;149(2):380–388. [PubMed] [Google Scholar]
  16. 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]
  17. 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]
  18. Harriman G. R., Lycke N. Y., Elwood L. J., Strober W. T lymphocytes that express CD4 and the alpha beta-T cell receptor but lack Thy-1. Preferential localization in Peyer's patches. J Immunol. 1990 Oct 15;145(8):2406–2414. [PubMed] [Google Scholar]
  19. Jung T. M., Gallatin W. M., Weissman I. L., Dailey M. O. Down-regulation of homing receptors after T cell activation. J Immunol. 1988 Dec 15;141(12):4110–4117. [PubMed] [Google Scholar]
  20. Kaiserlian D., Vidal K., MacDonald H. R., Grosjean I. Mouse intestinal epithelial cells express the self superantigen Mls1a. Eur J Immunol. 1993 Oct;23(10):2717–2720. doi: 10.1002/eji.1830231053. [DOI] [PubMed] [Google Scholar]
  21. Kennedy J. D., Pierce C. W., Lake J. P. Extrathymic T cell maturation. Phenotypic analysis of T cell subsets in nude mice as a function of age. J Immunol. 1992 Mar 15;148(6):1620–1629. [PubMed] [Google Scholar]
  22. 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]
  23. Kilshaw P. J., Murant S. J. Expression and regulation of beta 7(beta p) integrins on mouse lymphocytes: relevance to the mucosal immune system. Eur J Immunol. 1991 Oct;21(10):2591–2597. doi: 10.1002/eji.1830211041. [DOI] [PubMed] [Google Scholar]
  24. Ledbetter J. A., Rouse R. V., Micklem H. S., Herzenberg L. A. T cell subsets defined by expression of Lyt-1,2,3 and Thy-1 antigens. Two-parameter immunofluorescence and cytotoxicity analysis with monoclonal antibodies modifies current views. J Exp Med. 1980 Aug 1;152(2):280–295. doi: 10.1084/jem.152.2.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lögdberg L., Shevach E. M. Role of the Ly 1 antigen in interleukin 1-induced thymocyte activation. Eur J Immunol. 1985 Oct;15(10):1007–1013. doi: 10.1002/eji.1830151009. [DOI] [PubMed] [Google Scholar]
  26. Ohteki T., MacDonald H. R. Expression of the CD28 costimulatory molecule on subsets of murine intestinal intraepithelial lymphocytes correlates with lineage and responsiveness. Eur J Immunol. 1993 Jun;23(6):1251–1255. doi: 10.1002/eji.1830230609. [DOI] [PubMed] [Google Scholar]
  27. Poussier P., Edouard P., Lee C., Binnie M., Julius M. Thymus-independent development and negative selection of T cells expressing T cell receptor alpha/beta in the intestinal epithelium: evidence for distinct circulation patterns of gut- and thymus-derived T lymphocytes. J Exp Med. 1992 Jul 1;176(1):187–199. doi: 10.1084/jem.176.1.187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Poussier P., Teh H. S., Julius M. Thymus-independent positive and negative selection of T cells expressing a major histocompatibility complex class I restricted transgenic T cell receptor alpha/beta in the intestinal epithelium. J Exp Med. 1993 Dec 1;178(6):1947–1957. doi: 10.1084/jem.178.6.1947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Reem G. H., Carding S., Reinherz E. L. Lymphokine synthesis is induced in human thymocytes by activation of the CD 2 (T11) pathway. J Immunol. 1987 Jul 1;139(1):130–134. [PubMed] [Google Scholar]
  30. Roberts K., Kilshaw P. J. The mucosal T cell integrin alpha M290 beta 7 recognizes a ligand on mucosal epithelial cell lines. Eur J Immunol. 1993 Jul;23(7):1630–1635. doi: 10.1002/eji.1830230735. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Rocha B., von Boehmer H., Guy-Grand D. Selection of intraepithelial lymphocytes with CD8 alpha/alpha co-receptors by self-antigen in the murine gut. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5336–5340. doi: 10.1073/pnas.89.12.5336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Shirai T., Abe M., Yagita H., Okumura K., Morse H. C., 3rd, Davidson W. F. The expanded populations of CD4-CD8- T cell receptor alpha/beta+ T cells associated with the lpr and gld mutations are CD2-. J Immunol. 1990 May 15;144(10):3756–3761. [PubMed] [Google Scholar]
  34. Taguchi T., Aicher W. K., Fujihashi K., Yamamoto M., McGhee J. R., Bluestone J. A., Kiyono H. Novel function for intestinal intraepithelial lymphocytes. Murine CD3+, gamma/delta TCR+ T cells produce IFN-gamma and IL-5. J Immunol. 1991 Dec 1;147(11):3736–3744. [PubMed] [Google Scholar]
  35. Takimoto H., Yoshikai Y., Kishihara K., Matsuzaki G., Kuga H., Otani T., Nomoto K. Stimulation of all T cells bearing V beta 1, V beta 3, V beta 11 and V beta 12 by staphylococcal enterotoxin A. Eur J Immunol. 1990 Mar;20(3):617–621. doi: 10.1002/eji.1830200323. [DOI] [PubMed] [Google Scholar]
  36. Van Houten N., Mixter P. F., Wolfe J., Budd R. C. CD2 expression on murine intestinal intraepithelial lymphocytes is bimodal and defines proliferative capacity. Int Immunol. 1993 Jun;5(6):665–672. doi: 10.1093/intimm/5.6.665. [DOI] [PubMed] [Google Scholar]
  37. White J., Herman A., Pullen A. M., Kubo R., Kappler J. W., Marrack P. The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell. 1989 Jan 13;56(1):27–35. doi: 10.1016/0092-8674(89)90980-x. [DOI] [PubMed] [Google Scholar]
  38. Yagita H., Nakamura T., Karasuyama H., Okumura K. Monoclonal antibodies specific for murine CD2 reveal its presence on B as well as T cells. Proc Natl Acad Sci U S A. 1989 Jan;86(2):645–649. doi: 10.1073/pnas.86.2.645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yokoyama W. M., Maxfield S. R., Shevach E. M. Very early (VEA) and very late (VLA) activation antigens have distinct functions in T lymphocyte activation. Immunol Rev. 1989 Jun;109:153–176. doi: 10.1111/j.1600-065x.1989.tb00024.x. [DOI] [PubMed] [Google Scholar]
  40. de Waal Malefyt R., Verma S., Bejarano M. T., Ranes-Goldberg M., Hill M., Spits H. CD2/LFA-3 or LFA-1/ICAM-1 but not CD28/B7 interactions can augment cytotoxicity by virus-specific CD8+ cytotoxic T lymphocytes. Eur J Immunol. 1993 Feb;23(2):418–424. doi: 10.1002/eji.1830230218. [DOI] [PubMed] [Google Scholar]

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

RESOURCES