B cell-intrinsic CXCR3 drives efficient generation of ectopic pulmonary germinal center responses to influenza A virus infection.

Chemotactic receptors involved in generation of ectopic pulmonary germinal centers (GCs) within inducible bronchus-associated lymphoid tissue (iBALT) are poorly defined. Here, using CIBER Cxcr3-reporter mice, we demonstrate that the prototypical type 1 inflammatory chemokine receptor CXCR3 is highly induced in influenza A virus (IAV)-reactive B cells in the mediastinal lymph node, spleen, lung, peripheral blood, and airways following intranasal infection. Notably, elevated Cxcr3 was observed in ectopic pulmonary germinal center B (GCB) cells in iBALT relative to their contemporaneous counterparts in secondary lymphoid organs across the timecourse of the response to IAV infection. Mice with a B cell-specific deletion of Cxcr3 displayed a 50 to 60% reduction in the frequency and number of ectopic GCB cells in the lungs at the peak of the response following IAV infection, relative to controls. Furthermore, in cotransfers, Cxcr3-deficient B cells were substantially outcompeted by their Cxcr3-sufficient counterparts for ectopic pulmonary GC participation, but were not impacted with respect to GCB cell frequencies in other compartments. Thus, the data elucidate the requirement of B cell-intrinsic CXCR3 expression for efficient generation of ectopic pulmonary GCB cell responses in iBALT following respiratory viral infection with IAV, a finding that broadens understanding of the molecular cues underpinning this key component of local protective humoral immunity to IAV.