Regulation of diabetes development by regulatory T cells in pancreatic islet antigen-specific TCR transgenic nonobese diabetic mice.
Nonobese diabetic (NOD) mice carrying a transgenic TCR from an islet Ag-specific CD4 T cell clone, BDC2.5, do not develop diabetes. In contrast, the same transgenic NOD mice on the SCID background develop diabetes within 4 wk after birth. Using a newly developed mAb specific for the BDC2.5 TCR, we examined the interaction between diabetogenic T cells and regulatory T cells in NOD.BDC transgenic mice. CD4 T cells from NOD.BDC mice, expressing high levels of the clonotype, transfer diabetes to NOD.SCID recipients. In contrast, CD4 T cells expressing low levels due to the expression of both transgenic and endogenous TCR alpha-chains inhibit diabetes transfer. The clonotype-low CD4 T cells appear late in the ontogeny in the thymus and peripheral lymphoid organs, coinciding with resistance to cyclophosphamide-induced diabetes. These results demonstrate that diabetic processes in NOD.BDC mice are regulated by a balance between diabetogenic T cells and regulatory T cells. In the absence of specific manipulation, regulatory T cell function seems to be dominant and mice remain diabetes free. Understanding of mechanisms by which regulatory T cells inhibit diabetogenic processes would provide means to prevent diabetes development in high-risk human populations.
Kanagawa
Osami
O
Department of Pathology and Immunology and Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. kanagawa@pathology.wustl.edu
Militech
Ana
A
Vaupel
Barbala A
BA
D019264:Adoptive Transfer; D000375:Aging / Q000235:genetics / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis; D000918:Antibody Specificity / Q000235:genetics; D001323:Autoantibodies / Q000096:biosynthesis / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology; D003520:Cyclophosphamide / Q000008:administration & dosage; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000209:etiology / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D016130:Immunophenotyping; D007274:Injections, Intraperitoneal; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000276:immunology
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell; D003520:Cyclophosphamide