T lineage precursors from diabetes-prone NOD mice exhibit defective alpha-beta and enhanced gamma-delta T cell development (99.20)

Abstract

Abstract Because defects in various T lineages have been suggested to contribute to autoimmune diabetes in NOD mice, we sought to determine if early T cell precursors from NOD mice exhibit developmental abnormalities, which might affect later T cell lineage choices and responses. We previously reported that early T cells from NOD.Rag-/- mice undergo a spontaneous breakthrough at the first TCR-dependent checkpoint, a trait that appears to map near to two diabetes susceptibility genetic regions. We have also found that purified early T cell subsets from wild-type NOD mice undergoing differentiation in vitro exhibit profound defects in the generation and maintenance of DP populations, while gamma-delta T cell development is enhanced. NOD thymocytes also exhibit defects in development to the DP stage in vivo. These results show that NOD T cells have a lineage-specific abnormality at the first TCR-dependent checkpoint, which may select for DP cells with skewed signaling and/or survival characteristics, potentially altering positive and negative selection thresholds, T lineage choices, peripheral responses, and autoimmunity. (Supported by Juvenile Diabetes Foundation International and NIH R01AI064590 (to MAY).)