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Division of Critical Care Medicine

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Healthy children are more likely than adults to develop severe viral pneumonia, which can lead to long-term impairments in cardiopulmonary function. Our group demonstrated that juvenile mice infected with influenza A virus (IAV) have equivalent viral clearance to adults but exhibit prolonged inflammation. In adults, regulatory T cells (Tregs) suppress inflammation and promote tissue repair, in part by limiting conventional T cell (Tcon) proliferation. Treg depletion in adult IAV infection exacerbates lung injury and inflammation. We hypothesize that juvenile Treg reparative function is impaired during IAV infection, contributing to prolonged inflammation and aberrant lung repair. To assess this, we compared the suppressive capacity of splenic Tregs from adult (8-14 weeks) and juvenile (25-28 days) mice using lymphocyte suppression assays. Juvenile FoxP3°'® mice were infected with a sublethal titer of [AV intratracheally and treated with diphtheria toxin beginning 5 days post-infection (dpi) to deplete Tregs. Mice were monitored for daily weight loss. Quantification of bronchoalveolar lavage fluid (BALF) IL-6 and Amphiregulin (AREG) by enzyme-linked immunosorbent assay and enumeration of lung immune cells using flow cytometry occurred at 7 dpi. Lungs were assessed by H&E and immunofluorescent microscopy staining for lung injury and epithelial repair markers at 14 dpi. Juvenile Tregs demonstrated reduced suppression of Tcon proliferation compared to adult Tregs. Treg-sufficient and Treg-deficient juvenile mice failed to reach the growth potential of uninfected mice. Depleting Tregs did not alter BALF IL-6, lung neutrophil, or AREG levels. Treg-sufficient and Treg-depleted mice exhibited dense cellular infiltration, keratin 5 (Krt5*) pods of disrupted alveolar epithelial architecture, and keratin 8 (Krt8") cells indicating stalled alveolar epithelial cell differentiation. These findings suggest juvenile Tregs are insufficient to mitigate inflammation and promote repair during severe viral pneumonia. Further understanding of age-related differences in Treg-mediated repair may inform strategies to improve recovery for children with severe viral pneumonia.

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Northwestern University

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Division of Critical Care Medicine