Human T-bet governs the generation of a unique subset of CD11c-high CD21-low B cells

High level expression of the transcription factor T-bet characterizes a phenotypically distinct murine B-cell population known as 'age-associated B cells' (ABCs). T-bet-deficient mice have reduced ABCs and impaired humoral immunity. We describe a patient with inherited T-bet deficiency and largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B-cell formation in vivo, and B-cell differentiation into Ig-producing plasmablasts in vitro. Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4 and IgE, and reduced IgG2, in vivo and in vitro. Moreover, T-bet is required for the in vivo and in vitro development of a unique subset of human B cells characterized by reduced expression of CD21, and the concomitantly high expression of CD19, CD20, CD11c, FCRL5, and T-bet, which share many features with murine ABCs. Mechanistically, human T-bet governs CD21loCD11chi B cell differentiation by controlling chromatin accessibility of lineage-defining genes in these cells: FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B and CXCR4. Thus, human T-bet is largely redundant for long-lived protective humoral memory, but is essential for the development of a unique subset of human CD11chi CD21lo B cells.