Genetic Control of T and B Lymphocyte Activation in Nonobese Diabetic Mice

• Published in: The Journal of immunology (1950) Vol. 167; no. 12; pp. 7169 - 7179
• Main Authors: Chiu, Priscilla P. L, Jevnikar, Anthony M, Danska, Jayne S
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-12-2001
• Subjects: Animals; Antigens, CD - analysis; Antigens, Differentiation, T-Lymphocyte - analysis; Antigens, Viral - genetics; Antigens, Viral - immunology; B-Lymphocytes - immunology; Cells, Cultured; Chromosome Mapping; Clonal Deletion; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Flow Cytometry; Genes, T-Cell Receptor beta; Immunoglobulin Variable Region - genetics; Lectins, C-Type; Lymphocyte Activation; Major Histocompatibility Complex; Mice; Mice, Inbred NOD; Proviruses - immunology; Receptors, Antigen, T-Cell - metabolism; Superantigens - genetics; Superantigens - immunology; T-Lymphocytes - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.12.7169

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.