Lung adventitial fibroblasts support type 2 Tregs to shape the response to influenza infection
Chang, A.; Balcerek, J.; Caryotakis, S.; Pyper, K.; Matatia, P.; Wells, E.; Tsukui, T.; Ewing-Crystal, N. A.; Merrill, E. D.; Mroz, N. M.; Dahlgren, M. W.; Cautivo, K.; Taruselli, M.; Nakao-Inoue, H.; Molofsky, A. V.; Sheppard, D.; Molofsky, A. B.
Show abstract
Viral pneumonias are lung infections that lead to both short- and long-term complications, including acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Lung stromal-immune interactions balance pathogen clearance with excessive immune-mediated injury, and healthy lung repair with necessary scarring. Here, we define the lung spatiotemporal stromal-immune response to Influenza A virus (IAV) infection, focusing on the underappreciated role of fibroblasts and their dynamic states. We used 3D quantitative microscopy and scRNAseq to identify IAV-driven fibroblast states, including inflammatory fibroblasts, profibrotic fibroblasts, and adventitial fibroblasts (AFs). Unexpectedly, loss of fibroblast TGF{beta} signaling led to early enhancement of immuno-modulatory AFs, driving activation of tissue-resident type 2 regulatory T cells (T2-Tregs) and ultimately improving lung functional outcomes. In vitro co-culture systems additionally revealed that AFs act as a niche to support T2-Tregs. Our data suggest an intimate fibroblast-immune crosstalk is required to temporally and spatially balance lung tissue inflammation and repair.
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