Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1996 Feb;64(2):569–575. doi: 10.1128/iai.64.2.569-575.1996

Influence of beta 2-microglobulin expression on gamma interferon secretion and target cell lysis by intraepithelial lymphocytes during intestinal Listeria monocytogenes infection.

M Emoto 1, O Neuhaus 1, Y Emoto 1, S H Kaufmann 1
PMCID: PMC173803  PMID: 8550209

Abstract

Numerous microbial pathogens, including Listeria monocytogenes, enter the host through the intestine. Although relatively little is known about the biological functions of intestinal intraepithelial lymphocytes (i-IEL), they are generally considered a first line of defense against intestinal infections. In the mouse, the vast majority of i-IEL express the CD8 coreceptor either as a CD8 alpha/alpha homodimer or as a CD8 alpha/beta heterodimer. The CD8 receptor of T-cell receptor TcR gamma/delta i-IEL is exclusively homodimeric, whereas the CD8-expressing TcR alpha/beta i-IEL segregate into equal fractions of CD8 alpha/alpha and CD8 alpha/beta cells. We infected beta 2-microglobulin (beta 2m)+/- mice (possessing all i-IEL populations) and beta 2m -/- mutant mice (lacking all CD8 alpha/beta + i-IEL and having few CD8 alpha/alpha + TcR alpha/beta i-IEL) with L. monocytogenes per os and determined their biological functions after TcR ligation with monoclonal antibodies. Cytolytic activities of TcR alpha/beta and TcR gamma/delta i-IEL from beta 2m +/- mice were not influenced by intestinal listeriosis. Cytolytic activities of TcR alpha/beta i-IEL were impaired in uninfected beta 2m -/- mice, but this reduction was reestablished as a consequence of intestinal listeriosis. Frequencies of gamma interferon (IFN-gamma)-producing TcR alpha/beta i-IEL in uninfected beta 2m -/- mice were reduced, compared with that in their heterozygous controls. Equally low frequencies of IFN-gamma-producing TcR gamma/delta i-IEL in beta 2M +/- and beta 2m-/- mutants were found. Listeriosis increased frequencies of INF-gamma-producing TcR alpha/beta and TcR gamma/delta i-IEL in both mouse strains. Most remarkably, the proportion of IFN-gamma-producing TcR gamma/delta i-IEL was elevated 10-fold in listeria-infected beta 2M -/- mice. Our findings show that the beta 2m-independent CD8 beta- i-IEL expressing either TcR alpha/beta or TcR gamma/delta are stimulated by intestinal listeriosis independent of regional beta 2m expression. We conclude that the three major CD8+ i-IEL populations are stimulated by intestinal listeriosis and that CD8 beta- i-IEL compensate for the total lack of CD8 beta+ i-IEL in beta 2M -/- mutant mice. Hence, in contrast to the peripheral immune system, which crucially depends on CD8 alpha/beta + TcR alpha/beta lymphocytes, the mucosal immune system can rely on additional lymphocytes expressing the CD8 alpha/alpha homodimer.

Full Text

The Full Text of this article is available as a PDF (265.5 KB).

Selected References

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

  1. Balk S. P., Ebert E. C., Blumenthal R. L., McDermott F. V., Wucherpfennig K. W., Landau S. B., Blumberg R. S. Oligoclonal expansion and CD1 recognition by human intestinal intraepithelial lymphocytes. Science. 1991 Sep 20;253(5026):1411–1415. doi: 10.1126/science.1716785. [DOI] [PubMed] [Google Scholar]
  2. Bandeira A., Mota-Santos T., Itohara S., Degermann S., Heusser C., Tonegawa S., Coutinho A. Localization of gamma/delta T cells to the intestinal epithelium is independent of normal microbial colonization. J Exp Med. 1990 Jul 1;172(1):239–244. doi: 10.1084/jem.172.1.239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barinaga M. Researchers find molecules that muzzle killer cells. Science. 1995 Apr 21;268(5209):367–368. doi: 10.1126/science.7716537. [DOI] [PubMed] [Google Scholar]
  4. Beckman E. M., Porcelli S. A., Morita C. T., Behar S. M., Furlong S. T., Brenner M. B. Recognition of a lipid antigen by CD1-restricted alpha beta+ T cells. Nature. 1994 Dec 15;372(6507):691–694. doi: 10.1038/372691a0. [DOI] [PubMed] [Google Scholar]
  5. Bendelac A., Lantz O., Quimby M. E., Yewdell J. W., Bennink J. R., Brutkiewicz R. R. CD1 recognition by mouse NK1+ T lymphocytes. Science. 1995 May 12;268(5212):863–865. doi: 10.1126/science.7538697. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. Fleming D. W., Cochi S. L., MacDonald K. L., Brondum J., Hayes P. S., Plikaytis B. D., Holmes M. B., Audurier A., Broome C. V., Reingold A. L. Pasteurized milk as a vehicle of infection in an outbreak of listeriosis. N Engl J Med. 1985 Feb 14;312(7):404–407. doi: 10.1056/NEJM198502143120704. [DOI] [PubMed] [Google Scholar]
  9. Golstein P., Goridis C., Schmitt-Verhulst A. M., Hayot B., Pierres A., van Agthoven A., Kaufmann Y., Eshhar Z., Pierres M. Lymphoid cell surface interaction structures detected using cytolysis-inhibiting monoclonal antibodies. Immunol Rev. 1982;68:5–42. doi: 10.1111/j.1600-065x.1982.tb01058.x. [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. 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]
  12. 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]
  13. Guy-Grand D., Vassalli P. Gut intraepithelial T lymphocytes. Curr Opin Immunol. 1993 Apr;5(2):247–252. doi: 10.1016/0952-7915(93)90012-h. [DOI] [PubMed] [Google Scholar]
  14. Haas W., Pereira P., Tonegawa S. Gamma/delta cells. Annu Rev Immunol. 1993;11:637–685. doi: 10.1146/annurev.iy.11.040193.003225. [DOI] [PubMed] [Google Scholar]
  15. Ishikawa H., Li Y., Abeliovich A., Yamamoto S., Kaufmann S. H., Tonegawa S. Cytotoxic and interferon gamma-producing activities of gamma delta T cells in the mouse intestinal epithelium are strain dependent. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8204–8208. doi: 10.1073/pnas.90.17.8204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kaufmann S. H. Immunity to intracellular bacteria. Annu Rev Immunol. 1993;11:129–163. doi: 10.1146/annurev.iy.11.040193.001021. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Lefrançois L. Extrathymic differentiation of intraepithelial lymphocytes: generation of a separate and unequal T-cell repertoire? Immunol Today. 1991 Dec;12(12):436–438. doi: 10.1016/0167-5699(91)90015-L. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Linnan M. J., Mascola L., Lou X. D., Goulet V., May S., Salminen C., Hird D. W., Yonekura M. L., Hayes P., Weaver R. Epidemic listeriosis associated with Mexican-style cheese. N Engl J Med. 1988 Sep 29;319(13):823–828. doi: 10.1056/NEJM198809293191303. [DOI] [PubMed] [Google Scholar]
  21. Mestecky J., McGhee J. R. Immunoglobulin A (IgA): molecular and cellular interactions involved in IgA biosynthesis and immune response. Adv Immunol. 1987;40:153–245. doi: 10.1016/s0065-2776(08)60240-0. [DOI] [PubMed] [Google Scholar]
  22. Möller S. A., Borrebaeck C. A. A filter immuno-plaque assay for the detection of antibody-secreting cells in vitro. J Immunol Methods. 1985 May 23;79(2):195–204. doi: 10.1016/0022-1759(85)90099-7. [DOI] [PubMed] [Google Scholar]
  23. Nagler-Anderson C., McNair L. A., Cradock A. Self-reactive, T cell receptor-gamma delta+, lymphocytes from the intestinal epithelium of weanling mice. J Immunol. 1992 Oct 1;149(7):2315–2322. [PubMed] [Google Scholar]
  24. Neuhaus O., Emoto M., Blum C., Yamamoto S., Kaufmann S. H. Control of thymus-independent intestinal intraepithelial lymphocytes by beta 2-microglobulin. Eur J Immunol. 1995 Aug;25(8):2332–2339. doi: 10.1002/eji.1830250832. [DOI] [PubMed] [Google Scholar]
  25. Porcelli S. A. The CD1 family: a third lineage of antigen-presenting molecules. Adv Immunol. 1995;59:1–98. doi: 10.1016/s0065-2776(08)60629-x. [DOI] [PubMed] [Google Scholar]
  26. Porcelli S., Brenner M. B., Greenstein J. L., Balk S. P., Terhorst C., Bleicher P. A. Recognition of cluster of differentiation 1 antigens by human CD4-CD8-cytolytic T lymphocytes. Nature. 1989 Oct 5;341(6241):447–450. doi: 10.1038/341447a0. [DOI] [PubMed] [Google Scholar]
  27. Porcelli S., Morita C. T., Brenner M. B. CD1b restricts the response of human CD4-8- T lymphocytes to a microbial antigen. Nature. 1992 Dec 10;360(6404):593–597. doi: 10.1038/360593a0. [DOI] [PubMed] [Google Scholar]
  28. Poussier P., Julius M. Maturation of T cells in the intestinal epithelium. Immunol Today. 1993 Mar;14(3):140–141. doi: 10.1016/0167-5699(93)90217-9. [DOI] [PubMed] [Google Scholar]
  29. Poussier P., Julius M. Thymus independent T cell development and selection in the intestinal epithelium. Annu Rev Immunol. 1994;12:521–553. doi: 10.1146/annurev.iy.12.040194.002513. [DOI] [PubMed] [Google Scholar]
  30. Prat M., Gribaudo G., Comoglio P. M., Cavallo G., Landolfo S. Monoclonal antibodies against murine gamma interferon. Proc Natl Acad Sci U S A. 1984 Jul;81(14):4515–4519. doi: 10.1073/pnas.81.14.4515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rácz P., Tenner K., Mérö E. Experimental Listeria enteritis. I. An electron microscopic study of the epithelial phase in experimental listeria infection. Lab Invest. 1972 Jun;26(6):694–700. [PubMed] [Google Scholar]
  32. Schlech W. F., 3rd, Lavigne P. M., Bortolussi R. A., Allen A. C., Haldane E. V., Wort A. J., Hightower A. W., Johnson S. E., King S. H., Nicholls E. S. Epidemic listeriosis--evidence for transmission by food. N Engl J Med. 1983 Jan 27;308(4):203–206. doi: 10.1056/NEJM198301273080407. [DOI] [PubMed] [Google Scholar]
  33. Schleussner C., Ceredig R. Analysis of intraepithelial lymphocytes from major histocompatibility complex (MHC)-deficient mice: no evidence for a role of MHC class II antigens in the positive selection of V delta 4+ gamma delta T cells. Eur J Immunol. 1993 Jul;23(7):1615–1622. doi: 10.1002/eji.1830230733. [DOI] [PubMed] [Google Scholar]
  34. Seder R. A., Paul W. E. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol. 1994;12:635–673. doi: 10.1146/annurev.iy.12.040194.003223. [DOI] [PubMed] [Google Scholar]
  35. Shawar S. M., Vyas J. M., Rodgers J. R., Rich R. R. Antigen presentation by major histocompatibility complex class I-B molecules. Annu Rev Immunol. 1994;12:839–880. doi: 10.1146/annurev.iy.12.040194.004203. [DOI] [PubMed] [Google Scholar]
  36. Sollid L. M., Kvale D., Brandtzaeg P., Markussen G., Thorsby E. Interferon-gamma enhances expression of secretory component, the epithelial receptor for polymeric immunoglobulins. J Immunol. 1987 Jun 15;138(12):4303–4306. [PubMed] [Google Scholar]
  37. Spitalny G. L., Havell E. A. Monoclonal antibody to murine gamma interferon inhibits lymphokine-induced antiviral and macrophage tumoricidal activities. J Exp Med. 1984 May 1;159(5):1560–1565. doi: 10.1084/jem.159.5.1560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Steiniger B., Falk P., Lohmüller M., van der Meide P. H. Class II MHC antigens in the rat digestive system. Normal distribution and induced expression after interferon-gamma treatment in vivo. Immunology. 1989 Dec;68(4):507–513. [PMC free article] [PubMed] [Google Scholar]
  39. Stroynowski I. Molecules related to class-I major histocompatibility complex antigens. Annu Rev Immunol. 1990;8:501–530. doi: 10.1146/annurev.iy.08.040190.002441. [DOI] [PubMed] [Google Scholar]
  40. Taguchi T., McGhee J. R., Coffman R. L., Beagley K. W., Eldridge J. H., Takatsu K., Kiyono H. Analysis of Th1 and Th2 cells in murine gut-associated tissues. Frequencies of CD4+ and CD8+ T cells that secrete IFN-gamma and IL-5. J Immunol. 1990 Jul 1;145(1):68–77. [PubMed] [Google Scholar]
  41. Teixeira H. C., Kaufmann S. H. Role of NK1.1+ cells in experimental listeriosis. NK1+ cells are early IFN-gamma producers but impair resistance to Listeria monocytogenes infection. J Immunol. 1994 Feb 15;152(4):1873–1882. [PubMed] [Google Scholar]
  42. Viney J. L., Kilshaw P. J., MacDonald T. T. Cytotoxic alpha/beta+ and gamma/delta+ T cells in murine intestinal epithelium. Eur J Immunol. 1990 Jul;20(7):1623–1626. doi: 10.1002/eji.1830200734. [DOI] [PubMed] [Google Scholar]
  43. Yamamoto S., Russ F., Teixeira H. C., Conradt P., Kaufmann S. H. Listeria monocytogenes-induced gamma interferon secretion by intestinal intraepithelial gamma/delta T lymphocytes. Infect Immun. 1993 May;61(5):2154–2161. doi: 10.1128/iai.61.5.2154-2161.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Zhang Z. Y., Michael J. G. Orally inducible immune unresponsiveness is abrogated by IFN-gamma treatment. J Immunol. 1990 Jun 1;144(11):4163–4165. [PubMed] [Google Scholar]
  45. Zijlstra M., Bix M., Simister N. E., Loring J. M., Raulet D. H., Jaenisch R. Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature. 1990 Apr 19;344(6268):742–746. doi: 10.1038/344742a0. [DOI] [PubMed] [Google Scholar]
  46. 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]
  47. von Boehmer H., Swat W., Kisielow P. Positive selection of immature alpha beta T cells. Immunol Rev. 1993 Oct;135:67–79. doi: 10.1111/j.1600-065x.1993.tb00644.x. [DOI] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES