Survival and pulmonary recuperation following Influenza A (IAV) infection requires a well-orchestrated balance between pro-inflammatory and regulatory cells of the immune response. IL-18, a member of the IL-1 family of alarmins, is abundantly released in the lungs during IAV infections where it promotes anti-viral T1 responses. However, there is cumulating evidence that T cells can also recognize IL-18, although the mechanisms involved remain ill-defined. Through genetic disruption of the IL-18 receptor, we demonstrate that IL-18 not only promotes pulmonary T1 responses, but also influences T function in the infected lungs. As the anti-viral response unfolds, T cells accumulating in the lungs express Helios, T-bet, CXCR3 and IL-18R1. Specifically, activated T cells acquire T-bet and IL-18R1 and produce IFNγ in the presence of IL-12. During IAV, IL-18R1 is required for T cells to control T17, but not T1, 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 cells require an IL-18 signal to specifically suppress IL-17A production by T17 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 cells to selectively favor T1 over T17 responses during T1-driven immune responses and provide a novel perspective into how IL-18 dictates the immune response during viral and parasitic infections.Copyright © 2023. Published by Elsevier Inc.
