IL-18 is required for the TH1-adaptation of TREG cells and the selective suppression of TH17 responses in acute and chronic infections

Abstract

Interleukin (IL)-18, a member of the IL-1 family of alarmins, is abundantly released in the lungs following influenza A (IAV) infections yet its role in orchestrating the local adaptive immune response remains ill defined. Through genetic disruption of the IL-18 receptor, we demonstrate that IL-18 not only promotes pulmonary T_H1 responses but also influences regulatory T cells (T_REG) function in the infected lungs. As the response unfolds, T_REG cells accumulating in the lungs express Helios, T-bet, CXCR3, and IL-18R1 and produce interferon γ in the presence of IL-12. During IAV, IL-18R1 is required for T_REG cells to control T_H17, but not T_H1, responses and promote a return to lung homeostasis, revealing a novel mechanism of selective suppression. Moreover, this observation was not limited to the lungs, as skin-localized T_REG cells require an IL-18 signal to specifically suppress IL-17A production by T_H17 and γδ T cells in a model of chronic cutaneous Leishmania major infection. Overall, these results uncover how IL-18 orchestrates the tissue adaptation of T_REG cells to selectively favor T_H1 over T_H17 responses during T_H1-driven immune responses and provide a novel perspective into how IL-18 dictates the immune response during viral and parasitic infections.