A defect in lineage fate decision during fetal thymic invariant NKT cell development may regulate susceptibility to type 1 diabetes.

A numerical and functional deficiency in invariant NKT (iNKT) cells detectable by 3 wk of age in the thymus and spleen mediates the pathogenesis of type 1 diabetes in NOD mice, but the stage of T cell development at which this deficiency first occurs is unknown. We report in this study that this deficiency develops after the CD4(+)CD8(+) double-positive stage of thymic T cell development and is due to a lineage-specific depletion of CD4(-)CD8(-) double-negative alphabeta T cells and iNKT cells from the thymus between embryonic day 18 and day 1 after birth. Thus, an inheritable defect in a lineage fate decision that elicits a deficiency in fetal thymic iNKT cell development may predispose to susceptibility to type 1 diabetes.