IL-6 mediates defense against influenza virus by promoting protective antibody responses but not innate inflammation

Influenza virus infection is a leading cause of morbidity and mortality worldwide, posing a significant public health problem. The pro-inflammatory cytokine interleukin-6 (IL-6) has been shown to promote defense against respiratory viral infection, while excessive IL-6 responses have been associated with severe pneumonia. Heterogenous expression of IL-6R and the IL-6-signal transducer subunit (gp130) across many cell types and different signaling modalities have made it difficult to define the precise role of the IL-6/IL-6R pathway in vivo. We generated multiple cell lineage-specific Il6ra-deficient mice and compared them to global Il6ra^-/- and Il-6^-/- mice to dissect the systemic and cell-intrinsic mechanisms for pneumonitis and control of influenza A virus (IAV) infection. Delayed viral clearance and severe morbidity in the global IL-6 knockouts were associated with reduced antibody responses, complement C3 and C5 production, and impaired T follicular helper (Tfh) cell generation. Mice lacking IL-6R exclusively in T cells phenocopied a defect in Tfh cell differentiation and antibody production, although susceptibility to IAV was only mildly affected. Mice lacking IL-6R specifically in B cells mounted normal antibody responses. Moreover, innate pro-inflammatory cytokine responses, myeloid cell infiltration, and adaptive immunity in the lung remained unaffected in Il6ra^fl/flLysM^Cr^e mice. Our results suggest that IL-6 mediates defense against IAV mainly by generating Tfh cells and promoting local C3 production, which together are required for eliciting protective antibody responses by B cells.