A transcriptionally distinct subset of influenza-specific effector memory B cells predicts long-lived antibody responses to vaccination in humans.

Seasonal influenza vaccination elicits hemagglutinin (HA)-specific memory B (Bmem) cells, and although multiple Bmem cell populations have been characterized, considerable heterogeneity exists. We found that HA-specific human Bmem cells differed in the expression of surface marker FcRL5 and transcriptional factor T-bet. FcRL5T-bet Bmem cells were transcriptionally similar to effector-like memory cells, while T-betFcRL5 Bmem cells exhibited stem-like central memory properties. FcRL5 Bmem cells did not express plasma-cell-commitment factors but did express transcriptional, epigenetic, metabolic, and functional programs that poised these cells for antibody production. Accordingly, HA T-bet Bmem cells at day 7 post-vaccination expressed intracellular immunoglobulin, and tonsil-derived FcRL5 Bmem cells differentiated more rapidly into antibody-secreting cells (ASCs) in vitro. The T-bet Bmem cell response positively correlated with long-lived humoral immunity, and clonotypes from T-bet Bmem cells were represented in the secondary ASC response to repeat vaccination, suggesting that this effector-like population predicts influenza vaccine durability and recall potential.