Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Mar 1;177(3):627–636. doi: 10.1084/jem.177.3.627

Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential

PMCID: PMC2190953  PMID: 8094734

Abstract

Diabetes was induced in a normal nonautoimmune rat strain by rendering the animals relatively T cell deficient using a protocol of adult thymectomy and sublethal gamma irradiation. All male rats and 70% of females developed an acute syndrome with severe loss of weight and hyperglycemia. Diabetes in these lymphopoenic rats was associated with extensive insulitis involving CD4+ and CD8+ T cells and macrophages. The CD8+ T cells were essential for the development of diabetes but not insulitis. The autoimmune diabetes and insulitis were completely prevented by the injection of a particular CD4+ T cell subset, isolated from healthy syngeneic donors, of the phenotype CD45RClow T cell receptor alpha/beta+ RT6+ Thy-1- OX-40-. Cells of this protective phenotype, which make up about 5% of thoracic duct lymphocytes, were found to provide help for secondary antibody responses and produce interleukin 2 (IL-2) and IL-4, but no interferon gamma, on in vitro activation. These data provide evidence for the presence of autoreactive T cells in the normal immune system of the rat and reveal that in the intact animal these cells are prevented from expressing their autoreactive potential by other T cells.

Full Text

The Full Text of this article is available as a PDF (1.3 MB).

Selected References

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

  1. Akbar A. N., Salmon M., Janossy G. The synergy between naive and memory T cells during activation. Immunol Today. 1991 Jun;12(6):184–188. doi: 10.1016/0167-5699(91)90050-4. [DOI] [PubMed] [Google Scholar]
  2. Arthur R. P., Mason D. T cells that help B cell responses to soluble antigen are distinguishable from those producing interleukin 2 on mitogenic or allogeneic stimulation. J Exp Med. 1986 Apr 1;163(4):774–786. doi: 10.1084/jem.163.4.774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barclay A. N. The localization of populations of lymphocytes defined by monoclonal antibodies in rat lymphoid tissues. Immunology. 1981 Apr;42(4):593–600. [PMC free article] [PubMed] [Google Scholar]
  4. Bendelac A., Carnaud C., Boitard C., Bach J. F. Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. J Exp Med. 1987 Oct 1;166(4):823–832. doi: 10.1084/jem.166.4.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brideau R. J., Carter P. B., McMaster W. R., Mason D. W., Williams A. F. Two subsets of rat T lymphocytes defined with monoclonal antibodies. Eur J Immunol. 1980 Aug;10(8):609–615. doi: 10.1002/eji.1830100807. [DOI] [PubMed] [Google Scholar]
  6. Butcher G. W. A list of monoclonal antibodies specific for alloantigens of the rat. J Immunogenet. 1987 Apr-Jun;14(2-3):163–176. doi: 10.1111/j.1744-313x.1987.tb00377.x. [DOI] [PubMed] [Google Scholar]
  7. Campbell I. L., Kay T. W., Oxbrow L., Harrison L. C. Essential role for interferon-gamma and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice. J Clin Invest. 1991 Feb;87(2):739–742. doi: 10.1172/JCI115055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chatelain R., Varkila K., Coffman R. L. IL-4 induces a Th2 response in Leishmania major-infected mice. J Immunol. 1992 Feb 15;148(4):1182–1187. [PubMed] [Google Scholar]
  9. Daynes R. A., Araneo B. A., Dowell T. A., Huang K., Dudley D. Regulation of murine lymphokine production in vivo. III. The lymphoid tissue microenvironment exerts regulatory influences over T helper cell function. J Exp Med. 1990 Apr 1;171(4):979–996. doi: 10.1084/jem.171.4.979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Debray-Sachs M., Carnaud C., Boitard C., Cohen H., Gresser I., Bedossa P., Bach J. F. Prevention of diabetes in NOD mice treated with antibody to murine IFN gamma. J Autoimmun. 1991 Apr;4(2):237–248. doi: 10.1016/0896-8411(91)90021-4. [DOI] [PubMed] [Google Scholar]
  11. Ellerman K. E., Like A. A. Staphylococcal enterotoxin-activated spleen cells passively transfer diabetes in BB/Wor rat. Diabetes. 1992 Apr;41(4):527–532. doi: 10.2337/diab.41.4.527. [DOI] [PubMed] [Google Scholar]
  12. Fiorentino D. F., Bond M. W., Mosmann T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. doi: 10.1084/jem.170.6.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. GOWANS J. L., KNIGHT E. J. THE ROUTE OF RE-CIRCULATION OF LYMPHOCYTES IN THE RAT. Proc R Soc Lond B Biol Sci. 1964 Jan 14;159:257–282. doi: 10.1098/rspb.1964.0001. [DOI] [PubMed] [Google Scholar]
  14. Gajewski T. F., Fitch F. W. Differential activation of murine TH1 and TH2 clones. Res Immunol. 1991 Jan;142(1):19–23. doi: 10.1016/0923-2494(91)90005-4. [DOI] [PubMed] [Google Scholar]
  15. Greiner D. L., Mordes J. P., Handler E. S., Angelillo M., Nakamura N., Rossini A. A. Depletion of RT6.1+ T lymphocytes induces diabetes in resistant biobreeding/Worcester (BB/W) rats. J Exp Med. 1987 Aug 1;166(2):461–475. doi: 10.1084/jem.166.2.461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hall B. M., Jelbart M. E., Gurley K. E., Dorsch S. E. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Mediation of specific suppression by T helper/inducer cells. J Exp Med. 1985 Nov 1;162(5):1683–1694. doi: 10.1084/jem.162.5.1683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Heinzel F. P., Sadick M. D., Holaday B. J., Coffman R. L., Locksley R. M. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989 Jan 1;169(1):59–72. doi: 10.1084/jem.169.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hsiung L., Barclay A. N., Brandon M. R., Sim E., Porter R. R. Purification of human C3b inactivator by monoclonal-antibody affinity chromatography. Biochem J. 1982 Apr 1;203(1):293–298. doi: 10.1042/bj2030293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hunt S. V., Fowler M. H. A repopulation assay for B and T lymphocyte stem cells employing radiation chimaeras. Cell Tissue Kinet. 1981 Jul;14(4):445–464. doi: 10.1111/j.1365-2184.1981.tb00551.x. [DOI] [PubMed] [Google Scholar]
  20. Hutchings P. R., Cooke A. The transfer of autoimmune diabetes in NOD mice can be inhibited or accelerated by distinct cell populations present in normal splenocytes taken from young males. J Autoimmun. 1990 Apr;3(2):175–185. doi: 10.1016/0896-8411(90)90139-j. [DOI] [PubMed] [Google Scholar]
  21. Jefferies W. A., Green J. R., Williams A. F. Authentic T helper CD4 (W3/25) antigen on rat peritoneal macrophages. J Exp Med. 1985 Jul 1;162(1):117–127. doi: 10.1084/jem.162.1.117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kampinga J., Groen H., Klatter F., Meedendorp B., Aspinall R., Roser R., Nieuwenhuis P. Post-thymic T cell development in rats: an update. Biochem Soc Trans. 1992 Feb;20(1):191–197. doi: 10.1042/bst0200191. [DOI] [PubMed] [Google Scholar]
  23. Kampinga J., Kroese F. G., Pol G. H., Opstelten D., Seijen H. G., Boot J. H., Roser B., Nieuwenhuis P., Aspinall R. RT7-defined alloantigens in rats are part of the leucocyte common antigen family. Scand J Immunol. 1990 Jun;31(6):699–710. doi: 10.1111/j.1365-3083.1990.tb02821.x. [DOI] [PubMed] [Google Scholar]
  24. Like A. A., Biron C. A., Weringer E. J., Byman K., Sroczynski E., Guberski D. L. Prevention of diabetes in BioBreeding/Worcester rats with monoclonal antibodies that recognize T lymphocytes or natural killer cells. J Exp Med. 1986 Oct 1;164(4):1145–1159. doi: 10.1084/jem.164.4.1145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lubaroff D. M., Rasmussen G. T., Hunt H. D. The RT6 T cell antigen: its role in the identification of functional subsets and in T cell activation. Transplant Proc. 1989 Apr;21(2):3251–3254. [PubMed] [Google Scholar]
  26. Magaud J. P., Sargent I., Clarke P. J., Ffrench M., Rimokh R., Mason D. Y. Double immunocytochemical labeling of cell and tissue samples with monoclonal anti-bromodeoxyuridine. J Histochem Cytochem. 1989 Oct;37(10):1517–1527. doi: 10.1177/37.10.2476478. [DOI] [PubMed] [Google Scholar]
  27. Marcelletti J. F., Ohara J., Katz D. H. Collagen-induced arthritis in mice. Relationship of collagen-specific and total IgE synthesis to disease. J Immunol. 1991 Dec 15;147(12):4185–4191. [PubMed] [Google Scholar]
  28. Mason D. W., Williams A. F. The kinetics of antibody binding to membrane antigens in solution and at the cell surface. Biochem J. 1980 Apr 1;187(1):1–20. doi: 10.1042/bj1870001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mason D., Powrie F. Memory CD4+ T cells in man form two distinct subpopulations, defined by their expression of isoforms of the leucocyte common antigen, CD45. Immunology. 1990 Aug;70(4):427–433. [PMC free article] [PubMed] [Google Scholar]
  30. McCall M. N., Shotton D. M., Barclay A. N. Expression of soluble isoforms of rat CD45. Analysis by electron microscopy and use in epitope mapping of anti-CD45R monoclonal antibodies. Immunology. 1992 Jun;76(2):310–317. [PMC free article] [PubMed] [Google Scholar]
  31. McKnight A. J., Barclay A. N., Mason D. W. Molecular cloning of rat interleukin 4 cDNA and analysis of the cytokine repertoire of subsets of CD4+ T cells. Eur J Immunol. 1991 May;21(5):1187–1194. doi: 10.1002/eji.1830210514. [DOI] [PubMed] [Google Scholar]
  32. McMaster W. R., Williams A. F. Identification of Ia glycoproteins in rat thymus and purification from rat spleen. Eur J Immunol. 1979 Jun;9(6):426–433. doi: 10.1002/eji.1830090603. [DOI] [PubMed] [Google Scholar]
  33. Miller B. J., Appel M. C., O'Neil J. J., Wicker L. S. Both the Lyt-2+ and L3T4+ T cell subsets are required for the transfer of diabetes in nonobese diabetic mice. J Immunol. 1988 Jan 1;140(1):52–58. [PubMed] [Google Scholar]
  34. Miller J. F. The Croonian Lecture, 1992. The key role of the thymus in the body's defence strategies. Philos Trans R Soc Lond B Biol Sci. 1992 Jul 29;337(1279):105–124. doi: 10.1098/rstb.1992.0087. [DOI] [PubMed] [Google Scholar]
  35. Mordes J. P., Gallina D. L., Handler E. S., Greiner D. L., Nakamura N., Pelletier A., Rossini A. A. Transfusions enriched for W3/25+ helper/inducer T lymphocytes prevent spontaneous diabetes in the BB/W rat. Diabetologia. 1987 Jan;30(1):22–26. doi: 10.1007/BF01788902. [DOI] [PubMed] [Google Scholar]
  36. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  37. Nakhooda A. F., Like A. A., Chappel C. I., Murray F. T., Marliss E. B. The spontaneously diabetic Wistar rat. Metabolic and morphologic studies. Diabetes. 1977 Feb;26(2):100–112. doi: 10.2337/diab.26.2.100. [DOI] [PubMed] [Google Scholar]
  38. Parish C. R. The relationship between humoral and cell-mediated immunity. Transplant Rev. 1972;13:35–66. doi: 10.1111/j.1600-065x.1972.tb00059.x. [DOI] [PubMed] [Google Scholar]
  39. Paterson D. J., Jefferies W. A., Green J. R., Brandon M. R., Corthesy P., Puklavec M., Williams A. F. Antigens of activated rat T lymphocytes including a molecule of 50,000 Mr detected only on CD4 positive T blasts. Mol Immunol. 1987 Dec;24(12):1281–1290. doi: 10.1016/0161-5890(87)90122-2. [DOI] [PubMed] [Google Scholar]
  40. Peltz G. A role for CD4+ T-cell subsets producing a selective pattern of lymphokines in the pathogenesis of human chronic inflammatory and allergic diseases. Immunol Rev. 1991 Oct;123:23–35. doi: 10.1111/j.1600-065x.1991.tb00604.x. [DOI] [PubMed] [Google Scholar]
  41. Penhale W. J., Farmer A., McKenna R. P., Irvine W. J. Spontaneous thyroiditis in thymectomized and irradiated Wistar rats. Clin Exp Immunol. 1973 Oct;15(2):225–236. [PMC free article] [PubMed] [Google Scholar]
  42. Penhale W. J., Stumbles P. A., Huxtable C. R., Sutherland R. J., Pethick D. W. Induction of diabetes in PVG/c strain rats by manipulation of the immune system. Autoimmunity. 1990;7(2-3):169–179. doi: 10.3109/08916939008993389. [DOI] [PubMed] [Google Scholar]
  43. Penhale W. J., Young P. R. The influence of the normal microbial flora on the susceptibility of rats to experimental autoimmune thyroiditis. Clin Exp Immunol. 1988 May;72(2):288–292. [PMC free article] [PubMed] [Google Scholar]
  44. Powrie F., Mason D. OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset. J Exp Med. 1990 Dec 1;172(6):1701–1708. doi: 10.1084/jem.172.6.1701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Powrie F., Mason D. Subsets of rat CD4+ T cells defined by their differential expression of variants of the CD45 antigen: developmental relationships and in vitro and in vivo functions. Curr Top Microbiol Immunol. 1990;159:79–96. doi: 10.1007/978-3-642-75244-5_5. [DOI] [PubMed] [Google Scholar]
  46. Powrie F., Mason D. The MRC OX-22- CD4+ T cells that help B cells in secondary immune responses derive from naive precursors with the MRC OX-22+ CD4+ phenotype. J Exp Med. 1989 Mar 1;169(3):653–662. doi: 10.1084/jem.169.3.653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Romagnani S. Human TH1 and TH2 subsets: doubt no more. Immunol Today. 1991 Aug;12(8):256–257. doi: 10.1016/0167-5699(91)90120-I. [DOI] [PubMed] [Google Scholar]
  48. Sadick M. D., Heinzel F. P., Holaday B. J., Pu R. T., Dawkins R. S., Locksley R. M. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med. 1990 Jan 1;171(1):115–127. doi: 10.1084/jem.171.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Sakaguchi S., Sakaguchi N. Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease. J Immunol. 1989 Jan 15;142(2):471–480. [PubMed] [Google Scholar]
  50. Sakaguchi S., Sakaguchi N. Thymus and autoimmunity. Transplantation of the thymus from cyclosporin A-treated mice causes organ-specific autoimmune disease in athymic nude mice. J Exp Med. 1988 Apr 1;167(4):1479–1485. doi: 10.1084/jem.167.4.1479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Sakaguchi S., Takahashi T., Nishizuka Y. Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J Exp Med. 1982 Dec 1;156(6):1577–1586. doi: 10.1084/jem.156.6.1577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Scott P., Pearce E., Cheever A. W., Coffman R. L., Sher A. Role of cytokines and CD4+ T-cell subsets in the regulation of parasite immunity and disease. Immunol Rev. 1989 Dec;112:161–182. doi: 10.1111/j.1600-065x.1989.tb00557.x. [DOI] [PubMed] [Google Scholar]
  53. Silva J. S., Morrissey P. J., Grabstein K. H., Mohler K. M., Anderson D., Reed S. G. Interleukin 10 and interferon gamma regulation of experimental Trypanosoma cruzi infection. J Exp Med. 1992 Jan 1;175(1):169–174. doi: 10.1084/jem.175.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Spickett G. P., Brandon M. R., Mason D. W., Williams A. F., Woollett G. R. MRC OX-22, a monoclonal antibody that labels a new subset of T lymphocytes and reacts with the high molecular weight form of the leukocyte-common antigen. J Exp Med. 1983 Sep 1;158(3):795–810. doi: 10.1084/jem.158.3.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Sugihara S., Maruo S., Tsujimura T., Tarutani O., Kohno Y., Hamaoka T., Fujiwara H. Autoimmune thyroiditis induced in mice depleted of particular T cell subsets. III. Analysis of regulatory cells suppressing the induction of thyroiditis. Int Immunol. 1990;2(4):343–351. doi: 10.1093/intimm/2.4.343. [DOI] [PubMed] [Google Scholar]
  56. Swain S. L., Bradley L. M., Croft M., Tonkonogy S., Atkins G., Weinberg A. D., Duncan D. D., Hedrick S. M., Dutton R. W., Huston G. Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development. Immunol Rev. 1991 Oct;123:115–144. doi: 10.1111/j.1600-065x.1991.tb00608.x. [DOI] [PubMed] [Google Scholar]
  57. Taguchi O., Nishizuka Y. Experimental autoimmune orchitis after neonatal thymectomy in the mouse. Clin Exp Immunol. 1981 Nov;46(2):425–434. [PMC free article] [PubMed] [Google Scholar]
  58. Todd J. A. A protective role of the environment in the development of type 1 diabetes? Diabet Med. 1991 Dec;8(10):906–910. doi: 10.1111/j.1464-5491.1991.tb01528.x. [DOI] [PubMed] [Google Scholar]
  59. Todd J. A., Aitman T. J., Cornall R. J., Ghosh S., Hall J. R., Hearne C. M., Knight A. M., Love J. M., McAleer M. A., Prins J. B. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature. 1991 Jun 13;351(6327):542–547. doi: 10.1038/351542a0. [DOI] [PubMed] [Google Scholar]
  60. Vonderheide R. H., Hunt S. V. Comparison of IgD+ and IgD- thoracic duct B lymphocytes as germinal center precursor cells in the rat. Int Immunol. 1991 Dec;3(12):1273–1281. doi: 10.1093/intimm/3.12.1273. [DOI] [PubMed] [Google Scholar]
  61. Woollett G. R., Barclay A. N., Puklavec M., Williams A. F. Molecular and antigenic heterogeneity of the rat leukocyte-common antigen from thymocytes and T and B lymphocytes. Eur J Immunol. 1985 Feb;15(2):168–173. doi: 10.1002/eji.1830150211. [DOI] [PubMed] [Google Scholar]

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

RESOURCES