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 (TH1), TH2, and TH17) defined by expression of the key transcription factors T-bet, GATA3, and RORÎ 3t, respectively. Regulatory T (T reg) cells comprise a distinct anti-inflammatory lineage specified by the X-linked transcription factor Foxp3 (refs 2, 3). Paradoxically, some activated T reg cells express the aforementioned effector CD4 T cell transcription factors, which have been suggested to provide T reg cells with enhanced suppressive capacity. Whether expression of these factors in T reg 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 TH1-associated transcription factor T-bet in mouse T reg 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 reg cells - but not of T-bet expression in T reg cells - resulted in severe TH1 autoimmunity. Conversely, following depletion of T-bet - T reg cells, the remaining T-bet+cells specifically inhibited TH1 and CD8 T cell activation consistent with their co-localization with T-bet+effector T cells. These results suggest that T-bet+T reg cells have an essential immunosuppressive function and indicate that T reg cell functional heterogeneity is a critical feature of immunological tolerance.