Genetic control of T and B lymphocyte activation in nonobese diabetic mice.
Type 1 diabetes in nonobese diabetic (NOD) mice is characterized by the infiltration of T and B cells into pancreatic islets. T cells bearing the TCR Vbeta3 chain are disproportionately represented in the earliest stages of islet infiltration (insulitis) despite clonal deletion of most Vbeta3(+) immature thymocytes by the mammary tumor virus-3 (Mtv-3) superantigen (SAg). In this report we showed that a high frequency of NOD Vbeta3(+) T cells that escape deletion are activated in vivo and that this phenotype is linked to the Mtv-3 locus. One potential mechanism of SAg presentation to peripheral T cells is by activated B cells. Consistent with this idea, we found that NOD mice harbor a significantly higher frequency of activated B cells than nondiabetes-prone strains. These activated NOD B cells expressed cell surface molecules consistent with APC function. At the molecular level, the IgH repertoire of activated B cells in NOD mice was equivalent to resting B cells, suggesting a polyclonal response in vivo. Genetic analysis of the activated B cell phenotype showed linkage to Idd1, the NOD MHC haplotype (H-2(g7)). Finally, Vbeta3(+) thymocyte deletion and peripheral T cell activation did not require B cells, suggesting that other APC populations are sufficient to generate both Mtv-3-linked phenotypes. These data provide insight into the genetic regulation of NOD autoreactive lymphocyte activation that may contribute to failure of peripheral tolerance and the pathogenesis of type I diabetes.
Chiu
P P
PP
Program in Developmental Biology, Hospital for Sick Children Research Institute, Department of Surgery, University of Toronto, Toronto, Canada.
Jevnikar
A M
AM
Danska
J S
JS
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002874:Chromosome Mapping; D017637:Clonal Deletion; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005434:Flow Cytometry; D019674:Genes, T-Cell Receptor beta; D007135:Immunoglobulin Variable Region / Q000235:genetics; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D051379:Mice; D016688:Mice, Inbred NOD; D011533:Proviruses / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018089:Superantigens / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000956:Antigens, Viral; D007135:Immunoglobulin Variable Region; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; D000099192:CD69 Antigens