Project Summary Respiratory viral infections are a prevalent and ongoing threat to global health, as evidenced by seasonal Influenza A infections and the SARS-CoV-2 pandemic. Notably, the association between allergy and asthma and the severity of respiratory viral illness has been long observed but poorly understood. Group 2 innate lymphoid cells (ILC2s) and the adaptive counterpart Type 2 CD4 helper cells (Th2) have been extensively investigated for their role in allergic inflammation. Our group has described the localization of these type 2 lymphocytes (T2L) in non-lymphoid tissues, such as the lung, at rest and under allergic and mixed type 1-2 inflammation, observing localization near large airways and vessels at rest and expansion to the tissue parenchyma with allergic inflammation. Interestingly, in mixed type 1-2 inflammation, T2L parenchymal distribution is restricted due to Interferon gamma (IFNγ) signaling on T2L. My preliminary data demonstrates that IFNγ-mediated restriction also occurs following viral respiratory infection with Influenza A virus (IAV, PR8) and impacts mouse body weight and lung function. In parallel, I have demonstrated that loss IFNα/β signaling on T2Ls increases body weight loss and impairs lung function in IAV, potentially through a distinct mechanism. These data suggest that IFN-mediated restriction of T2L and T2L topography is critical for appropriate viral clearance and/or tissue repair in viral respiratory infection. Mechanisms of IFN-mediated restriction of T2L have been explored by many groups, including ours, however how this restriction of topography and counter-regulation of T1 immunity by T2L dictate the immune response to viral infection remains elusive. I hypothesize that IFN signaling regulates the topography and function of lung T2Ls in pulmonary viral infections. This proposal will define the topography of T1-T2 cross-regulation in the setting of pulmonary viral infection (Aim 1) and evaluate mechanism of interferon mediated restriction of type 2 lymphocytes (Aim 2). Completion of these aims will elucidate the role of canonical type 1 and type 2 cytokines in mediating tissue resident lymphocyte function in complex inflammation, providing novel mechanistic insight into how topography dictates immunity. Completion of this study provides a foundation for the development of precision therapeutics to selectively regulate lung resident lymphocytes subsets to impact the outcome of diverse lung diseases.