T-Bet Enables Tissue-Restricted B Cell Memory and Influenza Hemagglutinin Stalk-Specific Antibodies

T‐bet+ memory B cells: Generation, function, and fate

“…39,41,49,76 Similarly, T-bet + B cells are rare in healthy human blood but present in greater numbers following vaccination or infection: T-bet + B cells expand in frequency following live virus vaccination, are overrepresented in individuals with HIV, HCV, or malaria, and represent the primary HIV Env-specific memory B cell population in viremic individuals. T-bet-expressing B cells are exceedingly rare in young mice in the absence of infectious challenge, 27 but antigen-specific T-bet + B cells can be readily identified in the spleen following infection with E. muris or a diverse array of viruses.…”

“…T-bet is not necessary for switching to the IgG2 a/c isotype, 89 but depletion of T-bet-expressing B cells in mouse models of LCMV and influenza infection causes a significant loss of virus-specific IgG2 a , 39,76 indicating these cells are responsible for the majority of IgG2 a/c production. Studies of murine viral infections have identified differential antibody isotype regulation and epitope recognition between these memory populations, which appear to have functional consequences.…”

“…Studies of murine viral infections have identified differential antibody isotype regulation and epitope recognition between these memory populations, which appear to have functional consequences. 76 Loss of HA-specific IgG2 a via T-bet + B cell depletion abolishes serum antibody HA stalk reactivity, suggesting T-bet − B cells are unable to compensate by producing stalk-reactive antibody. Notably, T-bet − antigen-specific B cells remain following this depletion but are unable to compensate by generating virus-specific IgG2 a , and in the case of LCMV infection this results in loss of viral control.…”

“…T-bet is not necessary for switching to the IgG2 a/c isotype, 89 but depletion of T-bet-expressing B cells in mouse models of LCMV and influenza infection causes a significant loss of virus-specific IgG2 a , 39,76 indicating these cells are responsible for the majority of IgG2 a/c production. 76 The basis for skewed epitope recognition between T-bet + and T-bet − memory B cells is perplexing since human studies suggest the two subsets derive from common progenitors and display similar V H gene family usage. 39 Presumably, effective humoral responses to Th2-type infections would similarly be dependent upon antigen-specific IgG1 derived from T-bet -B cells and largely unaffected by T-bet + B cell depletion, but this experiment has yet to be performed.…”

“…39 Presumably, effective humoral responses to Th2-type infections would similarly be dependent upon antigen-specific IgG1 derived from T-bet -B cells and largely unaffected by T-bet + B cell depletion, but this experiment has yet to be performed. 76 Human T-bet + B cells are further absent from thoracic duct chyle fluid 76 of healthy donors, which contains the majority of lymphocytes recirculating from tissues and secondary lymphoid organs back into the blood stream, 90 suggesting that they do not enter or recirculate through the lymphatics. 76 Loss of HA-specific IgG2 a via T-bet + B cell depletion abolishes serum antibody HA stalk reactivity, suggesting T-bet − B cells are unable to compensate by producing stalk-reactive antibody.…”