Interleukin-33 activates regulatory T cells to suppress innate γδ T cell responses in the lung

Foxp3(+)regulatory T (T-reg) cells expressing the interleukin (IL)-33 receptor ST2 mediate tissue repair in response to IL-33. Whether T(reg)cells also respond to the alarmin IL-33 to regulate specific aspects of the immune response is not known. Here we describe an unexpected function of ST2(+)T(reg)cells in suppressing the innate immune response in the lung to environmental allergens without altering the adaptive immune response. Following allergen exposure, ST2(+)T(reg)cells were activated by IL-33 to suppress IL-17-producing gamma delta T cells. ST2 signaling in T(reg)cells induced Ebi3, a component of the heterodimeric cytokine IL-35 that was required for T(reg)cell-mediated suppression of gamma delta T cells. This response resulted in fewer eosinophil-attracting chemokines and reduced eosinophil recruitment into the lung, which was beneficial to the host in reducing allergen-induced inflammation. Thus, we define a fundamental role for ST2(+)T(reg)cells in the lung as a negative regulator of the early innate gamma delta T cell response to mucosal injury. Luster and colleagues show that T(reg)cells that reside in lung mucosa can respond to IL-33 upon allergen exposure and suppress innate cell responses. IL-33-activated ST2(+)T(reg)cells secrete IL-35, which suppresses IL-17 production by gamma delta T cells and lessens eosinophil recruitment into the lung.