TRAF3 regulates the effector function of regulatory T cells and humoral immune responses

Regulatory T cells (T_reg cells) control different aspects of immune responses, but how the effector functions of T_reg cells are regulated is incompletely understood. Here we identified TNF receptor-associated factor 3 (TRAF3) as a regulator of T_reg cell function. Treg cell-specific ablation of TRAF3 impaired CD4 T cell homeostasis, characterized by an increase in the Th1 type of effector/memory T cells. Moreover, the ablation of TRAF3 in T_reg cells resulted in increased antigen-stimulated activation of follicular T helper cells (T_FH cells), coupled with heightened formation of germinal centers and production of high-affinity IgG antibodies. Although the loss of TRAF3 did not reduce the overall frequency of T_reg cells, it attenuated the antigen-stimulated production of follicular T_reg cells (T_FR cells). TRAF3 signaling in T_reg cells was required to maintain high level expression of inducible co-stimulator (ICOS), which in turn was required for T_FR cell generation and inhibition of antibody responses. These findings establish TRAF3 as a mediator of T_reg cell function in the regulation of antibody responses and suggest a role for TRAF3 in mediating ICOS expression in T_reg cells.