title: Two mechanisms for the non-MHC-linked resistance to spontaneous autoimmunity.
abstract: Genetic susceptibility and resistance to most autoimmune disorders are associated with highly polymorphic genes of the MHC and with non-MHC-linked polygenic modifiers. It is known that non-MHC-linked polymorphisms can override or enhance the susceptibility to an autoimmune disease provided by pathogenic MHC genes, but the mechanisms remain elusive. In this study, we have followed the fate of two highly diabetogenic beta cell-specific T cell receptors (Kd and I-Ag7 restricted, respectively) in NOR/Lt mice, which are resistant to autoimmune diabetes despite expressing two copies of the diabetogenic MHC haplotype H-2g7. We show that at least two mechanisms of non-MHC-linked control of pathogenic T cells operate in these mice. One segregates as a recessive trait and is associated with a reduction in the peripheral frequency of diabetogenic CD8+ (but not CD4+) T cells. The other segregates as a dominant trait and is mediated by IL-4- and TGF-beta1-independent immune suppressive functions provided by lymphocytes that target diabetogenic CD4+ and CD8+ T cells, without causing their deletion, anergy, immune deviation, or ignorance. These results provide explanations as to how non-MHC-linked polymorphisms can override the susceptibility to an autoimmune disease provided by pathogenic MHC haplotypes, and demonstrate that protective non-MHC-linked genes may selectively target specific lymphoid cell types in cellularly complex autoimmune responses.
authors: Department of Microbiology and Infectious Diseases, Julia McFarlane Diabetes Research Centre, Faculty of Medicine, University of Calgary, Alberta, Canada.
authors: J
authors: J
authors: Verdaguer
authors: A
authors: A
authors: Amrani
authors: B
authors: B
authors: Anderson
authors: D
authors: D
authors: Schmidt
authors: P
authors: P
authors: Santamaria
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics; D017637:Clonal Deletion / Q000235:genetics; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D005260:Female; D019674:Genes, T-Cell Receptor beta / Q000276:immunology; D007108:Immune Tolerance; D007113:Immunity, Innate; D015847:Interleukin-4 / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018655:Lymphocyte Count; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D016212:Transforming Growth Factor beta; D015847:Interleukin-4