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 γδ 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 γδ 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 γδ T cell response to mucosal injury.