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. 1997 Aug;71(8):5782–5789. doi: 10.1128/jvi.71.8.5782-5789.1997

Enhanced mucosal and systemic immune responses to intestinal reovirus infection in beta2-microglobulin-deficient mice.

A S Major 1, C F Cuff 1
PMCID: PMC191832  PMID: 9223466

Abstract

Enteric infection of mice with respiratory enteric orphan virus (reovirus) type 1, strain Lang elicits both humoral and cellular immune responses. To investigate the role of CD8+, alpha/beta T-cell receptor (TCR)+ T cells in mucosal immunity to an enteric pathogen, we examined immune responses and viral clearance following enteric reovirus infection in C57BL/6, B6129F2, and beta2-microglobulin-deficient (beta2m-/-) mice. Analysis of Peyer's patch and lamina propria culture supernatants revealed a two- to threefold increase in levels of reovirus-specific immunoglobulin A in beta2m-/- mice compared to normal controls. These data corresponded to a similar increase in the frequency of virus-specific immunoglobulin A-producing cells in Peyer's patches and lamina propria and an increase in immunoglobulin G-producing cells in spleens from beta2m-/- mice compared to controls. These increased humoral immune responses were not due to a difference in B-cell populations because cell counts and flow cytometric analyses showed that beta2m-/- and control mice had similar numbers and percentages of B cells in mucosal and systemic tissues. Analysis of cytokine message by reverse transcriptase-PCR 5 and 10 days after infection revealed no difference in message level for transforming growth factor beta, gamma interferon, interleukin-4, interleukin-5, or interleukin-6 for all mouse strains. Virus tissue titers determined by plaque assay at 5 and 10 days after infection demonstrated that beta2m-/- mice cleared reovirus from the small intestines with the same efficiency as control mice. Collectively, these data suggest that CD8+, alpha/beta TCR+ T cells may regulate mucosal and systemic humoral immune responses to oral infection with reovirus.

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Selected References

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  1. BRAMBELL F. W., HEMMINGS W. A., MORRIS I. G. A THEORETICAL MODEL OF GAMMA-GLOBULIN CATABOLISM. Nature. 1964 Sep 26;203:1352–1354. doi: 10.1038/2031352a0. [DOI] [PubMed] [Google Scholar]
  2. Barkon M. L., Haller B. L., Virgin H. W., 4th Circulating immunoglobulin G can play a critical role in clearance of intestinal reovirus infection. J Virol. 1996 Feb;70(2):1109–1116. doi: 10.1128/jvi.70.2.1109-1116.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Battegay M., Moskophidis D., Waldner H., Bründler M. A., Fung-Leung W. P., Mak T. W., Hengartner H., Zinkernagel R. M. Impairment and delay of neutralizing antiviral antibody responses by virus-specific cytotoxic T cells. J Immunol. 1993 Nov 15;151(10):5408–5415. [PubMed] [Google Scholar]
  4. Bender B. S., Bell W. E., Taylor S., Small P. A., Jr Class I major histocompatibility complex-restricted cytotoxic T lymphocytes are not necessary for heterotypic immunity to influenza. J Infect Dis. 1994 Nov;170(5):1195–1200. doi: 10.1093/infdis/170.5.1195. [DOI] [PubMed] [Google Scholar]
  5. Bland P. W., Warren L. G. Antigen presentation by epithelial cells of the rat small intestine. II. Selective induction of suppressor T cells. Immunology. 1986 May;58(1):9–14. [PMC free article] [PubMed] [Google Scholar]
  6. Boll G., Reimann J. Lamina propria T cell subsets in the small and large intestine of euthymic and athymic mice. Scand J Immunol. 1995 Aug;42(2):191–201. doi: 10.1111/j.1365-3083.1995.tb03645.x. [DOI] [PubMed] [Google Scholar]
  7. Chardès T., Buzoni-Gatel D., Lepage A., Bernard F., Bout D. Toxoplasma gondii oral infection induces specific cytotoxic CD8 alpha/beta+ Thy-1+ gut intraepithelial lymphocytes, lytic for parasite-infected enterocytes. J Immunol. 1994 Nov 15;153(10):4596–4603. [PubMed] [Google Scholar]
  8. Chardès T., Velge-Roussel F., Mevelec P., Mevelec M. N., Buzoni-Gatel D., Bout D. Mucosal and systemic cellular immune responses induced by Toxoplasma gondii antigens in cyst orally infected mice. Immunology. 1993 Mar;78(3):421–429. [PMC free article] [PubMed] [Google Scholar]
  9. Chen Y., Inobe J., Weiner H. L. Induction of oral tolerance to myelin basic protein in CD8-depleted mice: both CD4+ and CD8+ cells mediate active suppression. J Immunol. 1995 Jul 15;155(2):910–916. [PubMed] [Google Scholar]
  10. Chen Y., Kuchroo V. K., Inobe J., Hafler D. A., Weiner H. L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science. 1994 Aug 26;265(5176):1237–1240. doi: 10.1126/science.7520605. [DOI] [PubMed] [Google Scholar]
  11. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Craig S. W., Cebra J. J. Peyer's patches: an enriched source of precursors for IgA-producing immunocytes in the rabbit. J Exp Med. 1971 Jul 1;134(1):188–200. doi: 10.1084/jem.134.1.188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cuff C. F., Cebra C. K., Rubin D. H., Cebra J. J. Developmental relationship between cytotoxic alpha/beta T cell receptor-positive intraepithelial lymphocytes and Peyer's patch lymphocytes. Eur J Immunol. 1993 Jun;23(6):1333–1339. doi: 10.1002/eji.1830230622. [DOI] [PubMed] [Google Scholar]
  15. Cuff C. F., Lavi E., Cebra C. K., Cebra J. J., Rubin D. H. Passive immunity to fatal reovirus serotype 3-induced meningoencephalitis mediated by both secretory and transplacental factors in neonatal mice. J Virol. 1990 Mar;64(3):1256–1263. doi: 10.1128/jvi.64.3.1256-1263.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Eichelberger M., Allan W., Zijlstra M., Jaenisch R., Doherty P. C. Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J Exp Med. 1991 Oct 1;174(4):875–880. doi: 10.1084/jem.174.4.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Emoto M., Neuhaus O., Emoto Y., Kaufmann S. H. Influence of beta 2-microglobulin expression on gamma interferon secretion and target cell lysis by intraepithelial lymphocytes during intestinal Listeria monocytogenes infection. Infect Immun. 1996 Feb;64(2):569–575. doi: 10.1128/iai.64.2.569-575.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Epstein S. L., Misplon J. A., Lawson C. M., Subbarao E. K., Connors M., Murphy B. R. Beta 2-microglobulin-deficient mice can be protected against influenza A infection by vaccination with vaccinia-influenza recombinants expressing hemagglutinin and neuraminidase. J Immunol. 1993 Jun 15;150(12):5484–5493. [PubMed] [Google Scholar]
  19. Ermak T. H., Owen R. L. Differential distribution of lymphocytes and accessory cells in mouse Peyer's patches. Anat Rec. 1986 Jun;215(2):144–152. doi: 10.1002/ar.1092150208. [DOI] [PubMed] [Google Scholar]
  20. Franco M. A., Greenberg H. B. Role of B cells and cytotoxic T lymphocytes in clearance of and immunity to rotavirus infection in mice. J Virol. 1995 Dec;69(12):7800–7806. doi: 10.1128/jvi.69.12.7800-7806.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Fujihashi K., McGhee J. R., Kweon M. N., Cooper M. D., Tonegawa S., Takahashi I., Hiroi T., Mestecky J., Kiyono H. gamma/delta T cell-deficient mice have impaired mucosal immunoglobulin A responses. J Exp Med. 1996 Apr 1;183(4):1929–1935. doi: 10.1084/jem.183.4.1929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ghetie V., Hubbard J. G., Kim J. K., Tsen M. F., Lee Y., Ward E. S. Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice. Eur J Immunol. 1996 Mar;26(3):690–696. doi: 10.1002/eji.1830260327. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. 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]
  25. Harriman G. R., Hörnqvist E., Lycke N. Y. Antigen-specific and polyclonal CD4+ lamina propria T-cell lines: phenotypic and functional characterization. Immunology. 1992 Jan;75(1):66–73. [PMC free article] [PubMed] [Google Scholar]
  26. Hou S., Doherty P. C., Zijlstra M., Jaenisch R., Katz J. M. Delayed clearance of Sendai virus in mice lacking class I MHC-restricted CD8+ T cells. J Immunol. 1992 Aug 15;149(4):1319–1325. [PubMed] [Google Scholar]
  27. Hyland L., Hou S., Coleclough C., Takimoto T., Doherty P. C. Mice lacking CD8+ T cells develop greater numbers of IgA-producing cells in response to a respiratory virus infection. Virology. 1994 Oct;204(1):234–241. doi: 10.1006/viro.1994.1527. [DOI] [PubMed] [Google Scholar]
  28. Hörnquist E., Grdic D., Mak T., Lycke N. CD8-deficient mice exhibit augmented mucosal immune responses and intact adjuvant effects to cholera toxin. Immunology. 1996 Feb;87(2):220–229. doi: 10.1046/j.1365-2567.1996.473536.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Israel E. J., Wilsker D. F., Hayes K. C., Schoenfeld D., Simister N. E. Increased clearance of IgG in mice that lack beta 2-microglobulin: possible protective role of FcRn. Immunology. 1996 Dec;89(4):573–578. doi: 10.1046/j.1365-2567.1996.d01-775.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kemeny D. M., Noble A., Holmes B. J., Diaz-Sanchez D. Immune regulation: a new role for the CD8+ T cell. Immunol Today. 1994 Mar;15(3):107–110. doi: 10.1016/0167-5699(94)90152-X. [DOI] [PubMed] [Google Scholar]
  31. Kramer D. R., Cebra J. J. Early appearance of "natural" mucosal IgA responses and germinal centers in suckling mice developing in the absence of maternal antibodies. J Immunol. 1995 Mar 1;154(5):2051–2062. [PubMed] [Google Scholar]
  32. Kramer D. R., Sutherland R. M., Bao S., Husband A. J. Cytokine mediated effects in mucosal immunity. Immunol Cell Biol. 1995 Oct;73(5):389–396. doi: 10.1038/icb.1995.61. [DOI] [PubMed] [Google Scholar]
  33. Lagoo A. S., Eldridge J. H., Lagoo-Deenadaylan S., Black C. A., Ridwan B. U., Hardy K. J., McGhee J. R., Beagley K. W. Peyer's patch CD8+ memory T cells secrete T helper type 1 and type 2 cytokines and provide help for immunoglobulin secretion. Eur J Immunol. 1994 Dec;24(12):3087–3092. doi: 10.1002/eji.1830241226. [DOI] [PubMed] [Google Scholar]
  34. Lehmann-Grube F., Löhler J., Utermöhlen O., Gegin C. Antiviral immune responses of lymphocytic choriomeningitis virus-infected mice lacking CD8+ T lymphocytes because of disruption of the beta 2-microglobulin gene. J Virol. 1993 Jan;67(1):332–339. doi: 10.1128/jvi.67.1.332-339.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lider O., Santos L. M., Lee C. S., Higgins P. J., Weiner H. L. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. II. Suppression of disease and in vitro immune responses is mediated by antigen-specific CD8+ T lymphocytes. J Immunol. 1989 Feb 1;142(3):748–752. [PubMed] [Google Scholar]
  36. London S. D., Cebra-Thomas J. A., Rubin D. H., Cebra J. J. CD8 lymphocyte subpopulations in Peyer's patches induced by reovirus serotype 1 infection. J Immunol. 1990 Apr 15;144(8):3187–3194. [PubMed] [Google Scholar]
  37. London S. D., Cebra J. J., Rubin D. H. Intraepithelial lymphocytes contain virus-specific, MHC-restricted cytotoxic cell precursors after gut mucosal immunization with reovirus serotype 1/Lang. Reg Immunol. 1989 Mar-Apr;2(2):98–102. [PubMed] [Google Scholar]
  38. London S. D., Rubin D. H., Cebra J. J. Gut mucosal immunization with reovirus serotype 1/L stimulates virus-specific cytotoxic T cell precursors as well as IgA memory cells in Peyer's patches. J Exp Med. 1987 Mar 1;165(3):830–847. doi: 10.1084/jem.165.3.830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Major A. S., Cuff C. F. Effects of the route of infection on immunoglobulin G subclasses and specificity of the reovirus-specific humoral immune response. J Virol. 1996 Sep;70(9):5968–5974. doi: 10.1128/jvi.70.9.5968-5974.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Mayer L., Shlien R. Evidence for function of Ia molecules on gut epithelial cells in man. J Exp Med. 1987 Nov 1;166(5):1471–1483. doi: 10.1084/jem.166.5.1471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. McDonald V., Deer R., Uni S., Iseki M., Bancroft G. J. Immune responses to Cryptosporidium muris and Cryptosporidium parvum in adult immunocompetent or immunocompromised (nude and SCID) mice. Infect Immun. 1992 Aug;60(8):3325–3331. doi: 10.1128/iai.60.8.3325-3331.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. McDonald V., Robinson H. A., Kelly J. P., Bancroft G. J. Immunity to Cryptosporidium muris infection in mice is expressed through gut CD4+ intraepithelial lymphocytes. Infect Immun. 1996 Jul;64(7):2556–2562. doi: 10.1128/iai.64.7.2556-2562.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Medesan C., Radu C., Kim J. K., Ghetie V., Ward E. S. Localization of the site of the IgG molecule that regulates maternofetal transmission in mice. Eur J Immunol. 1996 Oct;26(10):2533–2536. doi: 10.1002/eji.1830261038. [DOI] [PubMed] [Google Scholar]
  44. Muller D., Koller B. H., Whitton J. L., LaPan K. E., Brigman K. K., Frelinger J. A. LCMV-specific, class II-restricted cytotoxic T cells in beta 2-microglobulin-deficient mice. Science. 1992 Mar 20;255(5051):1576–1578. doi: 10.1126/science.1347959. [DOI] [PubMed] [Google Scholar]
  45. Nakagawa I., Takahashi I., Kiyono H., McGhee J. R., Hamada S. Oral immunization with the B subunit of the heat-labile enterotoxin of Escherichia coli induces early Th1 and late Th2 cytokine expression in Peyer's patches. J Infect Dis. 1996 Jun;173(6):1428–1436. doi: 10.1093/infdis/173.6.1428. [DOI] [PubMed] [Google Scholar]
  46. Offit P. A., Dudzik K. I. Rotavirus-specific cytotoxic T lymphocytes appear at the intestinal mucosal surface after rotavirus infection. J Virol. 1989 Aug;63(8):3507–3512. doi: 10.1128/jvi.63.8.3507-3512.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Pamer E. G., Harty J. T., Bevan M. J. Precise prediction of a dominant class I MHC-restricted epitope of Listeria monocytogenes. Nature. 1991 Oct 31;353(6347):852–855. doi: 10.1038/353852a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Pollock R. R., French D. L., Metlay J. P., Birshtein B. K., Scharff M. D. Intravascular metabolism of normal and mutant mouse immunoglobulin molecules. Eur J Immunol. 1990 Sep;20(9):2021–2027. doi: 10.1002/eji.1830200921. [DOI] [PubMed] [Google Scholar]
  49. Popov S., Hubbard J. G., Kim J., Ober B., Ghetie V., Ward E. S. The stoichiometry and affinity of the interaction of murine Fc fragments with the MHC class I-related receptor, FcRn. Mol Immunol. 1996 Apr;33(6):521–530. doi: 10.1016/0161-5890(96)00004-1. [DOI] [PubMed] [Google Scholar]
  50. Raulet D. H. MHC class I-deficient mice. Adv Immunol. 1994;55:381–421. doi: 10.1016/s0065-2776(08)60514-3. [DOI] [PubMed] [Google Scholar]
  51. Rubin D., Weiner H. L., Fields B. N., Greene M. I. Immunologic tolerance after oral administration of reovirus: requirement for two viral gene products for tolerance induction. J Immunol. 1981 Oct;127(4):1697–1701. [PubMed] [Google Scholar]
  52. Sabath D. E., Broome H. E., Prystowsky M. B. Glyceraldehyde-3-phosphate dehydrogenase mRNA is a major interleukin 2-induced transcript in a cloned T-helper lymphocyte. Gene. 1990 Jul 16;91(2):185–191. doi: 10.1016/0378-1119(90)90087-8. [DOI] [PubMed] [Google Scholar]
  53. Santos L. M., al-Sabbagh A., Londono A., Weiner H. L. Oral tolerance to myelin basic protein induces regulatory TGF-beta-secreting T cells in Peyer's patches of SJL mice. Cell Immunol. 1994 Sep;157(2):439–447. doi: 10.1006/cimm.1994.1240. [DOI] [PubMed] [Google Scholar]
  54. Shirahata T., Yamashita T., Ohta C., Goto H., Nakane A. CD8+ T lymphocytes are the major cell population involved in the early gamma interferon response and resistance to acute primary Toxoplasma gondii infection in mice. Microbiol Immunol. 1994;38(10):789–796. doi: 10.1111/j.1348-0421.1994.tb01858.x. [DOI] [PubMed] [Google Scholar]
  55. Simister N. E., Mostov K. E. An Fc receptor structurally related to MHC class I antigens. Nature. 1989 Jan 12;337(6203):184–187. doi: 10.1038/337184a0. [DOI] [PubMed] [Google Scholar]
  56. Spriggs M. K., Koller B. H., Sato T., Morrissey P. J., Fanslow W. C., Smithies O., Voice R. F., Widmer M. B., Maliszewski C. R. Beta 2-microglobulin-, CD8+ T-cell-deficient mice survive inoculation with high doses of vaccinia virus and exhibit altered IgG responses. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6070–6074. doi: 10.1073/pnas.89.13.6070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Sztein M. B., Tanner M. K., Polotsky Y., Orenstein J. M., Levine M. M. Cytotoxic T lymphocytes after oral immunization with attenuated vaccine strains of Salmonella typhi in humans. J Immunol. 1995 Oct 15;155(8):3987–3993. [PubMed] [Google Scholar]
  58. Takahashi I., Marinaro M., Kiyono H., Jackson R. J., Nakagawa I., Fujihashi K., Hamada S., Clements J. D., Bost K. L., McGhee J. R. Mechanisms for mucosal immunogenicity and adjuvancy of Escherichia coli labile enterotoxin. J Infect Dis. 1996 Mar;173(3):627–635. doi: 10.1093/infdis/173.3.627. [DOI] [PubMed] [Google Scholar]
  59. VanCott J. L., Staats H. F., Pascual D. W., Roberts M., Chatfield S. N., Yamamoto M., Coste M., Carter P. B., Kiyono H., McGhee J. R. Regulation of mucosal and systemic antibody responses by T helper cell subsets, macrophages, and derived cytokines following oral immunization with live recombinant Salmonella. J Immunol. 1996 Feb 15;156(4):1504–1514. [PubMed] [Google Scholar]
  60. Weiner H. L., Friedman A., Miller A., Khoury S. J., al-Sabbagh A., Santos L., Sayegh M., Nussenblatt R. B., Trentham D. E., Hafler D. A. Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu Rev Immunol. 1994;12:809–837. doi: 10.1146/annurev.iy.12.040194.004113. [DOI] [PubMed] [Google Scholar]
  61. Wolf J. L., Rubin D. H., Finberg R., Kauffman R. S., Sharpe A. H., Trier J. S., Fields B. N. Intestinal M cells: a pathway for entry of reovirus into the host. Science. 1981 Apr 24;212(4493):471–472. doi: 10.1126/science.6259737. [DOI] [PubMed] [Google Scholar]
  62. 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]

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