Level of self-reactivity modulates functional potential of effector T cells in autoimmune diabetes.

Abstract

Abstract T cell infiltration and accumulation in pancreatic islets during autoimmune diabetes is largely dependent on TCR specificity for beta cell antigens. However, it is not fully clear whether the level of self-reactivity is an important determinant of T cell function in autoimmunity. We observed that CD5 expression is proportional to the level of self-reactivity based on Nur77-GFP reporter of TCR signaling and insulin tetramer staining of islet infiltrating T cells. Using RNAseq profiling, TCR sequencing, and cell transfer diabetes model we show that CD5 segregates functionally and transcriptionally distinct effector T cells. Transfer of CD5hi islet infiltrating T cells resulted in accelerated diabetes development compared to CD5lo cells (8 weeks vs. 11 weeks post transfer), suggesting that both T cell populations are able to re-infiltrate the pancreas and cause beta cell destruction, but CD5hi T cells exhibit increased pathogenicity. RNAseq analysis showed an increase in expression of Lag3 and FR4 in CD5hi cells, consistent with their increased activation and subsequent induction of regulatory and tolerogenic pathways. However, cell intrinsic negative regulators did not suppress IFNg production in CD5hi T cells, which was significantly higher compared to CD5lo cells. Our findings show that the strength of TCR reactivity to beta cell antigens is an important determinant of T cell pathogenicity in autoimmune diabetes.