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

Abstract

B cells expressing the transcription factor T-bet have emerged as participants in a number of protective and pathogenic immune responses. T-bet⁺ B cells characteristically differentiate in response to combined Toll-like receptor and cytokine signaling, contribute to protective immunity against intracellular pathogens via IgG2_a/c production and antibody-independent mechanisms, and are prone to produce autoantibodies. Despite recent advances, a number of questions remain regarding the basic biology of T-bet⁺ B cells and their functional niche within the immune system. Herein, we review the discovery and defining characteristics of the T-bet⁺ B cell subset in both mice and humans. We further discuss their origins, the basis for their persistence, and their potential fate in vivo. Evidence indicates that T-bet⁺ B cells represent a distinct, germinal center-derived memory population that may serve as an important therapeutic target for the improvement of humoral immunity and prevention of autoimmunity.

Keywords: T-bet+ B cells; humoral autoimmunity; intracellular pathogens; memory B cells; plasma cells; tissue-resident memory B cells.

Figure 1:

Origin, fate, and function of T-bet+ B cells: Microorganisms and apoptotic debris can trigger signaling downstream of nucleic acid receptors. Based on the cytokine milieu present, these signals can induce (via IFNg/IL-21) or inhibit (via IL-4) T-bet expression in B cells. Evidence suggests a requirement for cognate help and germinal center-dependent formation of T-bet+ B cells, but T-bet-expressing B cells can develop extrafollicularly under certain conditions. T-bet expression drives class switching to IgG2a/c in mice or IgG1 in humans, whereas T-bet- B cells favor other isotypes, such as IgA. T-bet+ memory B cells are persistent, most likely due to self-renewal, and can be progenitors of plasma cells or, upon re-challenge, differentiate into other effector cell lineages. Because of their persistence and roles promoting antibody secretion and other B cell effector functions, T-bet+ B cells are key players in pathogenic and protective humoral immunity.