Ikaros silences the ifnγ gene during T cell anergy and T helper polarization (88.14)

Abstract Ikaros is a zinc finger transcription factor required for lymphocyte development, but recent studies indicate that this factor also regulates peripheral T cell function. Our previous studies showed that Ikaros is a major repressor of il2 gene expression during the induction of T cell anergy, and in the present study, we have examined the role of Ikaros in ifnγ gene expression in CD4+ T cells. We find that Ikaros binds to the endogenous ifnγ and tbx21 loci, an event associated with increased DNA methylation at the ifnγ gene. Loss of Ikaros function in vitro resulted in increased IFNγ production by anergic T cells and Th2 cells, and was reinforced in Th2 cells by dysregulated expression of Tbet. Loss of Ikaros function in vivo led to an inappropriate Th1 response to the Th2 parasite S. mansoni, and also led to increased ifnγ gene expression and fatal intestinal immunopathology in a DSS model of colitis. Our results show that Ikaros is an important transcriptional repressor of Tbet and IFNγ expression, and further establish a role for Ikaros in T cell tolerance and T helper polarization.