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 naive CD4 T cells into functionally distinct subsets of effector T cells (T helper 1 (T1), T2, and T17) defined by expression of the key transcription factors T-bet, GATA3, and RORγt, respectively. Regulatory T (T) cells comprise a distinct anti-inflammatory lineage specified by the X-linked transcription factor Foxp3 (refs 2, 3). Paradoxically, some activated T cells express the aforementioned effector CD4 T cell transcription factors, which have been suggested to provide T cells with enhanced suppressive capacity. Whether expression of these factors in T cells-as in 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 expression of the T1-associated transcription factor T-bet in mouse T cells, 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 T cells-but not of T-bet expression in T cells-resulted in severe T1 autoimmunity. Conversely, following depletion of T-bet T cells, the remaining T-bet cells specifically inhibited T1 and CD8 T cell activation consistent with their co-localization with T-bet effector T cells. These results suggest that T-bet T cells have an essential immunosuppressive function and indicate that T cell functional heterogeneity is a critical feature of immunological tolerance.