SUMMARY Regulatory T (Treg) cells suppress immune responses to a broad range of non-microbial and microbial antigens and indirectly limit immune inflammation-in-flicted tissue damage by employing multiple mechanisms of suppression. Here, we demonstrate that selective Treg cell deficiency in amphiregulin leads to severe acute lung damage and decreased blood oxygen concentration during influenza virus infection without any measureable alterations in Treg cell suppressor function, antiviral immune responses, or viral load. This tissue repair modality is mobilized in Treg cells in response to inflammatory mediator IL-18 or alarmin IL-33, but not by TCR signaling that is required for suppressor function. These results suggest that, during infectious lung injury, Treg cells have a major direct and non-redundant role in tissue repair and maintenance—distinct from their role in suppression of immune responses and inflammation—and that these two essential Treg cell functions are invoked by separable cues.

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 (TH1, TH2, and TH17) 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 Foxp32, 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 capacity4, 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 TH1-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 TH1 autoimmunity. Conversely, following depletion of T-bet-negative Treg cells, remaining T-bet+ cells specifically inhibited TH1 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.

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