Signals that drive T-bet expression in B cells

Abstract

Transcription factors regulate various developmental and functional aspects of B cells. T-bet is a recently appreciated transcription factor associated with "Age-associated B cells" or ABCs, the development of autoimmunity, and viral infections. T-bet expression is favored by nucleic acid-containing antigens and immune complexes and is regulated by interplay between various cytokines, notably, the TFH cytokines IL-21, IL-4 and IFNγ. Adaptive signals by themselves cannot upregulate T-bet; however, they have a synergistic effect on induction of T-bet by innate receptors. The functional role of T-bet+ B cells is unclear, although it is known that T-bet promotes class switching to IgG2a/c. It is likely T-bet serves dichotomous roles in B cells, promoting pathogenic autoreactive antibodies on one hand but mediating microbial immunity on the other, making it a target of interest in both therapeutic and prophylactic settings.

Keywords: B cell; IFN-gamma; IL21; Signalling; T-bet; TLR.

Fig. 1.

Signals driving T-bet expression in B cells. The three signaling systems that govern the initiation of Tbet expression and subsequent differentiative fates in B cells are shown. Necessary signals are shown with bold arrows. Question marks indicate that further analogous signals may remain undiscovered. Pathogen-associated or self ligands that engage innate receptors, like TLRs, are required to poise B cells for T-bet expression. TLRs that have been directly implicated in T-bet expression are listed, although other DAMPs and PAMPs may also provide such signals. Actual transcription of T-bet requires the appropriate cytokine milieu and associated STAT signaling. To date, IL-21 and IFN-γ singly and synergistically induce T-bet expression in poised cells. In contrast, IL-4 can block IL21-driven T-bet expression. Other cytokines signaling through similar Jak/STAT pathways have not been investigated; they could shed light on how T-bet expression is regulated in different infections, autoimmunity or inflammation. Adaptive signaling- BCR and co-stimulation – are not sufficient to induce T-bet expression. However, BCR-mediated delivery of nucleic acids containing antigens amplifies TLR-driven T-bet expression. Cognate CD4, while not sufficient, appears to be essential for T-bet expression, but can foster a GC versus plasma cell fate decisions among T-bet+ cells.