Identification of a role for Casz1 in the control of T helper differentiation and inflammation

Abstract

Abstract While T helper (Th) cells constitute a critical arm of adaptive immune system and are important for host defense, unregulated expansion and imbalance in Th effector subsets contribute to inflammatory disorders. Here we show that Casz1, whose function is previously unknown in CD4+ T cells, determines the balance between various Th subsets. As systemic knockout mice are embryonically lethal, we generated conditional CD4 Casz1 knockout mice. Conditional deletion of Casz1 in CD4+ T cells significantly inhibits Th17 cell differentiation, but promotes Th1 differentiation. Loss of Casz1 in CD4+ T cells lowers susceptibility to experimental autoimmune encephalomyelitis, consistent with the reduced frequency of Th17 cells, despite an increase in Th1 cells. These results underscore the critical role of Casz1 in determining Th17 lineage differentiation in vivo. Transcriptome analyses of Casz1 deficient CD4+ T cells show a signature consistent with defective Th17 differentiation but enhanced Th1 differentiation. Taken together, these data reveal Casz1 as a new T helper cell regulator having important clinical implications for autoimmune inflammation.