Regulation of CD11c+ T-bet+ IgM+ Memory B-cells by TNFα

Abstract

Abstract Our studies of ehrlichial infection have identified a population of CD11c+ T-bet+ IgM memory B-cells that arise within 30 days post-infection. We and others have shown that CD11c+ T-bet+B cells require for their development or function a number of factors, including T-bet, IFNγ, CD4 T-cells, IL-21, and TLRs. Here, we addressed a possible role for TNFα in the generation of CD11c+ T-bet+IgM memory B-cells, because aside from being a major inflammatory cytokine, it can regulate germinal center development, and mediate apoptosis. We observed an 8-fold increase in the number of CD11c+IgM memory B-cells (also CD73+) in TNFα-deficient mice, relative to wild-type mice, on day 16 post-infection. The B cell population persisted at much higher frequency and number on day 30 post-infection. The changes in the IgM memory cell population were associated with a concomitant 10-fold relative increase in the frequency of GL7+ CD38lo CD95+germinal center B cells in TNFα-deficient mice. These latter data contrast with published studies that have reported that TNFα is required for GC development, suggesting that the requirement we have observed for TNFα is context-dependent. These data suggest that there may be a positive relationship between GC development and generation of CD11c+ IgM memory cells, and that TNFα may act to mediate IgM memory cell homeostasis by regulating apoptosis. Ongoing studies will address mechanisms whereby TNFα contributes to the genesis and maintenance of CD11c+ T-bet+IgM memory B-cells.