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 RORγt, respectively. Regulatory T (Treg) cells comprise a distinct anti-inflammatory lineage specified by the X-linked transcription factor Foxp3 (refs 2, 3). Paradoxically, some activated Treg cells express the aforementioned effector CD4 T cell transcription factors, which have been suggested to provide Treg cells with enhanced suppressive capacity. Whether expression of these factors in Treg 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 Treg 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 Treg cells-but not of T-bet expression in Treg cells-resulted in severe TH1 autoimmunity. Conversely, following depletion of T-bet- Treg 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+ Treg cells have an essential immunosuppressive function and indicate that Treg cell functional heterogeneity is a critical feature of immunological tolerance.

Central European Institute of Technology Masaryk University Kamenice 753 5 Brno 62500 Czech Republic

Department of Comparative Medicine University of Washington School of Medicine Seattle Washington 98195 USA

Howard Hughes Medical Institute Immunology Program and Ludwig Center Memorial Sloan Kettering Cancer Center New York New York 10065 USA

Molecular Cytology Core Facility Memorial Sloan Kettering Cancer Center New York New York 10065 USA

Pirogov Russian National Research Medical University Ostrovityanova 1 Moscow 117997 Russia

Shemyakin Ovchinnikov Institute of Bioorganic Chemistry RAS Miklukho Maklaya 16 10 Moscow 117997 Russia

Nat Rev Immunol. 2017 Jul;17(7):401. doi: 10.1038/nri.2017.68. PubMed

Nature. 2017 Sep 20;550(7674):142. doi: 10.1038/nature24013. PubMed

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