Stability and function of regulatory T cells expressing the transcription factor T-bet

Adaptive immune responses are tailored to different types of pathogens through differentiation of naïve CD4 T cells into functionally distinct subsets of effector T cells (T(H)1, T(H)2, and T(H)17) defined by expression of key transcription factors (TFs)(1). Regulatory T (Treg) cells comprise a distinct anti-inflammatory lineage specified by the X-linked TF Foxp3(2, 3). Paradoxically, some activated Treg cells express the aforementioned effector CD4 T cell TFs, which have been suggested to endow Treg cells with enhanced suppressive capacity(4, 5, 6). Whether expression of these factors in Treg cells—akin to effector T cells—is indicative of heterogeneity of functionally discrete and stable differentiation states, or conversely may be readily reversible, is unknown. Here, we demonstrate that in Treg cells expression of the T(H)1-associated TF T-bet, induced at steady state and following infection, gradually becomes highly stable even under non-permissive conditions. Loss-of-function or elimination of T-bet-expressing Treg cells—but not of T-bet in Treg cells—resulted in severe T(H)1 autoimmunity. Conversely, following depletion of T-bet-negative Treg cells, remaining T-bet(+) cells specifically inhibited T(H)1 and CD8 T cell activation in agreement with their co-localization with T-bet(+) effector T cells. These results suggest an essential immunosuppressive function for T-bet(+) Treg cells and indicate that Treg cell functional heterogeneity is a critical feature of immune tolerance.