A Distinct Function of Regulatory T Cells in Tissue Protection

Regulatory T (Treg) cells suppress immune responses to a broad range of non-microbial and microbial antigens and indirectly limit immune inflammation-inflicted 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. [Display omitted] •Treg cells serve as a major early source of amphiregulin during influenza infection•Amphiregulin expression in Treg cells is dispensable for their suppressor function•Amphiregulin deficiency in Treg cells results in severe damage of infected lungs•Treg cell production of amphiregulin is IL-18/IL-33 dependent but TCR independent Regulatory T cells have a major direct and non-redundant role in tissue repair and maintenance that is distinct from their role in suppression of immune responses and inflammation and is invoked by a different set of cues.