Regulatory T cell-derived IL-1Ra suppresses the innate response to respiratory viral infection

Abstract

Regulatory T (T_reg) cell modulation of adaptive immunity and tissue homeostasis is well described; however, less is known about T_reg cell-mediated regulation of the innate immune response. Here we show that deletion of ST2, the receptor for interleukin (IL)-33, on T_reg cells increased granulocyte influx into the lung and increased cytokine production by innate lymphoid and γδ T cells without alteration of adaptive immunity to influenza. IL-33 induced high levels of the interleukin-1 receptor antagonist (IL-1Ra) in ST2⁺ T_reg cells and deletion of IL-1Ra in T_reg cells increased granulocyte influx into the lung. T_reg cell-specific deletion of ST2 or IL-1Ra improved survival to influenza, which was dependent on IL-1. Adventitial fibroblasts in the lung expressed high levels of the IL-1 receptor and their chemokine production was suppressed by T_reg cell-produced IL-1Ra. Thus, we define a new pathway where IL-33-induced IL-1Ra production by tissue T_reg cells suppresses IL-1-mediated innate immune responses to respiratory viral infection.