Distinct Inflammatory Programming of Thoracic Cavity White Adipose Immune Cells Regulates Influenza Pathogenesis

BACKGROUND: Obesity-associated inflammation in white adipose tissue (WAT) worsens outcomes of influenza A virus (IAV) infection. A recently identified thoracic cavity WAT (tcWAT) supports IAV replication. However, tcWAT's immune cell composition, functional properties and role in IAV disease severity remains unclear. METHODS: Using a mouse model of diet-induced obesity, flow cytometry and single cell RNA-sequencing, we compared tcWAT with lung-distal visceral WAT assessing immune cell composition, transcriptomic profiles, inflammatory potential, and impact on IAV pathogenesis. RESULTS: At baseline, tcWAT was uniquely enriched for immune cells with heightened proinflammatory capacity and exhibited a striking predominance of lymphocytic populations, including immature and Satb1+ T cells, the latter expressing gene signatures associated with elevated T cell activation. Transfer of tcWAT immune cells into IAV infected recipients accelerated IAV disease severity. IAV infection robustly reshaped tcWAT immune landscape, driving expansion of a B cell population expressing Zbtb32 and upregulating genes involved in immune regulation and antiviral responses. Concurrently, IAV infection reduced immune populations linked to neutrophil regulation in tcWAT, while these same populations were expanded in the lung. CONCLUSIONS: These findings identify lung-proximal tcWAT as a distinct inflammatory tissue that may amplify pathogenic immune responses during IAV infection.