The adaptor molecule TRAF3 restrains the lineage determination of thymic regulatory T cells by modulating interleukin-2 receptor signaling

The number of Foxp3(+) regulatory T (T(reg)) cells must be tightly controlled to efficiently suppress autoimmunity while not impairing normal immune responses. Here we show that the adapter molecule TRAF3 is intrinsically required for restraining lineage determination of thymic T(reg) cells. T cell-specific TRAF3 deficiency resulted in a 2-3 fold increase of T(reg) cell frequency, due to more efficient transition from T precursors to Foxp3(+) T(reg) cells. TRAF3 dampened interleukin-2 (IL-2) signaling by facilitating recruitment of T cell protein tyrosine phosphatase (TCPTP) to the IL-2 receptor complex, resulting in dephosphorylation of the signaling molecules Jak1 and Jak3 and negative regulation of Jak-STAT5 signaling. Our results identify a role for TRAF3 as an important negative regulator of IL-2 receptor signaling that impacts T(reg) cell development.