A key role for Fas ligand expressed on B cells in initiation of autoimmune diabetes (99.17)

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Abstract Type-1 diabetes (T1D) is an organ specific autoimmune disease that affects children. T, B and dendritic cells infiltrate islets in the early stage of disease leading to insulitis followed by islet destruction and hyperglycemia. Development of T1D in non-obese diabetic (NOD) mice is completely inhibited by gld or lpr mutations of Fas and FasL, respectively, even though mutant mice develop T cell lymphoproliferation and the Fas pathway is not essential for T cell activation. Recently, we have shown heterozygous gld mutation (gld/+) provides complete protection without causing lymphoproliferation. Using NOD-gld/+ mouse as a model, we found that the protection is not due to deletion of autoreactive T cells or switching of T helper polarization. Islet-reactive BDC2.5 TCR transgenic CD4 T cells transferred into NOD-gld/+ mice were efficiently primed in the pancreatic lymph nodes but failed to accumulate in the pancreas. FasL deficiency selectively reduced expression of CD40 and frequency of B cells in the pancreas. Transfer of wild type B cells into NOD-gld/+ mice results in mobilization of endogenous T cells particularly CD8 T cells and of co-transferred BDC2.5 T cells resulting in severe insulitis. These results provide the first evidence that B cells play an essential role in gld-mediated protection from T1D and that expression of functional FasL on B cells is key for initiation insulitis. Supported by grants from AHA and JDRF.