Abstract
The association of major histocompatibility complex genes with autoimmune diseases is firmly established, but the mechanisms by which these genes confer resistance or susceptibility remain controversial. The controversy extends to the nonobese diabetic (NOD) mouse that develops disease similar to human insulin-dependent diabetes mellitus. The transgenic incorporation of certain class II major histocompatibility complex genes protects NOD mice from diabetes, and clonal deletion or functional silencing of autoreactive T cells has been proposed as the mechanism by which these molecules provide protection. We show that neither thymic deletion nor anergy of autoreactive T cells occurs in NOD mice transgenic for I-Ak. Autoreactive T cells are present, functional, and can transfer diabetes to appropriate NOD-recipient mice.
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- Acha-Orbea H., McDevitt H. O. The first external domain of the nonobese diabetic mouse class II I-A beta chain is unique. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2435–2439. doi: 10.1073/pnas.84.8.2435. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bendelac A., Boitard C., Bach J. F., Carnaud C. Neonatal induction of allogeneic tolerance prevents T cell-mediated autoimmunity in NOD mice. Eur J Immunol. 1989 Apr;19(4):611–616. doi: 10.1002/eji.1830190406. [DOI] [PubMed] [Google Scholar]
- Böhme J., Schuhbaur B., Kanagawa O., Benoist C., Mathis D. MHC-linked protection from diabetes dissociated from clonal deletion of T cells. Science. 1990 Jul 20;249(4966):293–295. doi: 10.1126/science.2115690. [DOI] [PubMed] [Google Scholar]
- Charlton B., Bacelj A., Slattery R. M., Mandel T. E. Cyclophosphamide-induced diabetes in NOD/WEHI mice. Evidence for suppression in spontaneous autoimmune diabetes mellitus. Diabetes. 1989 Apr;38(4):441–447. doi: 10.2337/diab.38.4.441. [DOI] [PubMed] [Google Scholar]
- Christianson S. W., Shultz L. D., Leiter E. H. Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes. 1993 Jan;42(1):44–55. doi: 10.2337/diab.42.1.44. [DOI] [PubMed] [Google Scholar]
- Fowell D., Mason D. 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. J Exp Med. 1993 Mar 1;177(3):627–636. doi: 10.1084/jem.177.3.627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hengartner H., Odermatt B., Schneider R., Schreyer M., Wälle G., MacDonald H. R., Zinkernagel R. M. Deletion of self-reactive T cells before entry into the thymus medulla. Nature. 1988 Nov 24;336(6197):388–390. doi: 10.1038/336388a0. [DOI] [PubMed] [Google Scholar]
- Kappler J. W., Wade T., White J., Kushnir E., Blackman M., Bill J., Roehm N., Marrack P. A T cell receptor V beta segment that imparts reactivity to a class II major histocompatibility complex product. Cell. 1987 Apr 24;49(2):263–271. doi: 10.1016/0092-8674(87)90567-8. [DOI] [PubMed] [Google Scholar]
- Klein J. What causes immunological nonresponsiveness? Immunol Rev. 1984 Oct;81:177–202. doi: 10.1111/j.1600-065x.1984.tb01110.x. [DOI] [PubMed] [Google Scholar]
- Lo D., Sprent J. Identity of cells that imprint H-2-restricted T-cell specificity in the thymus. Nature. 1986 Feb 20;319(6055):672–675. doi: 10.1038/319672a0. [DOI] [PubMed] [Google Scholar]
- Lund T., O'Reilly L., Hutchings P., Kanagawa O., Simpson E., Gravely R., Chandler P., Dyson J., Picard J. K., Edwards A. Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain. Nature. 1990 Jun 21;345(6277):727–729. doi: 10.1038/345727a0. [DOI] [PubMed] [Google Scholar]
- MacDonald H. R., Schneider R., Lees R. K., Howe R. C., Acha-Orbea H., Festenstein H., Zinkernagel R. M., Hengartner H. T-cell receptor V beta use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature. 1988 Mar 3;332(6159):40–45. doi: 10.1038/332040a0. [DOI] [PubMed] [Google Scholar]
- Miyazaki T., Uno M., Uehira M., Kikutani H., Kishimoto T., Kimoto M., Nishimoto H., Miyazaki J., Yamamura K. Direct evidence for the contribution of the unique I-ANOD to the development of insulitis in non-obese diabetic mice. Nature. 1990 Jun 21;345(6277):722–724. doi: 10.1038/345722a0. [DOI] [PubMed] [Google Scholar]
- Nepom G. T. A unified hypothesis for the complex genetics of HLA associations with IDDM. Diabetes. 1990 Oct;39(10):1153–1157. doi: 10.2337/diab.39.10.1153. [DOI] [PubMed] [Google Scholar]
- Nishimoto H., Kikutani H., Yamamura K., Kishimoto T. Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. 1987 Jul 30-Aug 5Nature. 328(6129):432–434. doi: 10.1038/328432a0. [DOI] [PubMed] [Google Scholar]
- Schwartz R. H. Acquisition of immunologic self-tolerance. Cell. 1989 Jun 30;57(7):1073–1081. doi: 10.1016/0092-8674(89)90044-5. [DOI] [PubMed] [Google Scholar]
- Serreze D. V., Leiter E. H. Development of diabetogenic T cells from NOD/Lt marrow is blocked when an allo-H-2 haplotype is expressed on cells of hemopoietic origin, but not on thymic epithelium. J Immunol. 1991 Aug 15;147(4):1222–1229. [PubMed] [Google Scholar]
- Slattery R. M., Kjer-Nielsen L., Allison J., Charlton B., Mandel T. E., Miller J. F. Prevention of diabetes in non-obese diabetic I-Ak transgenic mice. Nature. 1990 Jun 21;345(6277):724–726. doi: 10.1038/345724a0. [DOI] [PubMed] [Google Scholar]
- Todd J. A., Acha-Orbea H., Bell J. I., Chao N., Fronek Z., Jacob C. O., McDermott M., Sinha A. A., Timmerman L., Steinman L. A molecular basis for MHC class II--associated autoimmunity. Science. 1988 May 20;240(4855):1003–1009. doi: 10.1126/science.3368786. [DOI] [PubMed] [Google Scholar]
- Todd J. A., Bell J. I., McDevitt H. O. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature. 1987 Oct 15;329(6140):599–604. doi: 10.1038/329599a0. [DOI] [PubMed] [Google Scholar]
- Yamamura K., Miyazaki T., Uno M., Toyonaga T., Miyazaki J. Non-obese diabetic transgenic mouse. Springer Semin Immunopathol. 1992;14(2):115–125. doi: 10.1007/BF00195289. [DOI] [PubMed] [Google Scholar]