Interferon-y production by Tfh cells is required for CXCR3+pre-memory B cell differentiation and subsequent lung-resident memory B cell responses

Lung-resident memory B cells (lung-BRMs) differentiate into plasma cells after reinfection, providing enhanced pulmonary protection. Here, we investigated the determinants of lung-BRM differentiation upon influenza infection. Kinetic analyses revealed that influenza nucleoprotein (NP)-specific BRMs preferentially differentiated early after infection and required T follicular helper (Tfh) cell help. BRM differentiation tempo-rally coincided with transient interferon (IFN)-y production by Tfh cells. Depletion of IFN-y in Tfh cells pre-vented lung-BRM differentiation and impaired protection against heterosubtypic infection. IFN-y was required for expression of the transcription factor T-bet by germinal center (GC) B cells, which promoted dif-ferentiation of a CXCR3+ GC B cell subset that were precursors of lung-BRMs and CXCR3+ memory B cells in the mediastinal lymph node. Absence of IFN-y signaling or T-bet in GC B cells prevented CXCR3+ pre -mem-ory precursor development and hampered CXCR3+ memory B cell differentiation and subsequent lung-BRM responses. Thus, Tfh-cell-derived IFN-y is critical for lung-BRM development and pulmonary immunity, with implications for vaccination strategies targeting BRMs.