Expression of Helios is required for the differentiation of activated/effector T regulatory cells (IRC11P.438)

Abstract

Abstract Foxp3+ Regulatory T cells (Treg) suppress immune activation and play a critical role in the maintenance of self-tolerance. A subpopulation (70-80%) of Treg cells in both mouse and man express the transcription factor, Helios, but the role of Helios in Treg function is still unknown. Deletion of Helios expression in all T cells (CD4-Cre) or in early progenitors (Vav-Cre) did not result in immune dysfunction. As some studies have suggested that Helios might be expressed in activated T conventional cells, we generated mice with a conditional deletion (KO) of Helios in Treg. The selective deletion of Helios in Tregs led to a slowly progressive, systemic immune activation characterized by a Th1 profile, lymphadenopathy, splenomegaly, increased serum Ig and enhanced lymphoid follicle and germinal center formation in the absence of immune pathology. In vitro suppressive function of Helios KO Treg was normal, but KO Treg failed to differentiate into T follicular regulatory cells in vivo. While the absolute number of Treg in KO mice was enhanced, in competitive settings Helios deficient Tregs were at a striking disadvantage in the periphery. Notably, Helios KO Tregs with an activated (CD44hiCD62Llo) effector Treg phenotype were greatly decreased. Analysis of Helios KO Tregs revealed increased levels of several BH3 domain pro-apoptotic genes. These findings suggest that Helios plays a critical role in the development and/or survival of effector Tregs by repressing pro-apoptotic genes.