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2026

Proc Natl Acad Sci U S A . 2026 Jul 7;123(27):e2535787123. doi: 10.1073/pnas.2535787123. Epub 2026 Jun 30.

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

Timona S Tyllis, Todd S Norton, Caitlin Abbott, Dylan J McPeake, Kevin A Fenix, Jasmine J Wilson, Ervin E Kara, Kim L Good-Jacobson, Mohammed Alsharifi, Shaun R McColl, Iain Comerford

Research Centre for Infectious Diseases, School of Biological Sciences, Adelaide University, Adelaide, SA 5005, Australia. School of Medicine, College of Health, Adelaide University, Adelaide, SA 5000, Australia. Medical Oncology and the Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Central Adelaide Local Health Network, Woodville, SA 5011, Australia. Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.

Service type: Stock strains

Abstract

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.