T-bet enables tissue-restricted B cell memory and influenza hemagglutinin stalk-specific antibodies. Homo sapiens

We describe functionally distinct influenza hemagglutinin (HA)-specific memory B cell populations (MBCs) in mice and humans, distinguished by T-bet expression. In mice, both T-bet- and T-bet+ HA-specific B cells emerge early after infection, acquire the memory markers CD73, PD-L2 and CD80, and persist indefinitely. Moreover, T-bet- and T-bet+ MBCs are unequally partitioned in various tissues and undergo minimal interconversion, based on lineage tracing and IgH repertoire analyses. Further, T-bet+ MBCs can be subdivided into a recirculating T-betlo subset and a spleen-resident T-bethi subset. Human MBCs display similar features; whereas T-bet- and T-betlo MBCs are found in all secondary lymphoid tissues, T-bethi MBCs are exclusively found in spleen, blood, and bone marrow. Finally, B lineage T-bet expression is required for HA stalk-specific IgG2c antibodies and durable neutralizing titers to influenza. Together, these findings show T-bet expression is a stable and conserved feature that discriminates MBCs with distinct tissue distributions, recirculation properties, and epitope specificities.