Expression of CD40 identifies a unique pathogenic T cell population in type 1 diabetes

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Abstract
Juvenile diabetes (type 1) is an autoimmune disease in which CD4+ T cells play a major role in pathogenesis characterized by insulitis and β cell destruction leading to clinical hyperglycemia. To date, no marker for autoimmune T cells has been described, although it was previously demonstrated that autoimmune mice have a large population of CD4+ cells that express CD40. We show here that established, diabetogenic T cell clones of either the Th1 or Th2 phenotype are CD40-positive, whereas nondiabetogenic clones are CD40-negative. CD40 functionally signals T cell clones, inducing rapid activation of the transcription factor NFκB. We show that autoimmune diabetes-prone nonobese diabetic mice have high levels of CD40+CD4+ T cells in the thymus, spleen, and importantly, in the pancreas. Finally, as demonstrated by adoptive transfers, CD4+CD40+ cells infiltrate the pancreatic islets causing β-cell degranulation and ultimately diabetes.