The Transcription Factor T-bet Resolves Memory B Cell Subsets with Distinct Tissue Distributions and Antibody Specificities in Mice and Humans

Abstract

B cell subsets expressing the transcription factor T-bet are associated with humoral immune responses and autoimmunity. Here, we examined the anatomic distribution, clonal relationships, and functional properties of T-bet⁺ and T-bet^- memory B cells (MBCs) in the context of the influenza-specific immune response. In mice, both T-bet^- and T-bet⁺ hemagglutinin (HA)-specific B cells arose in germinal centers, acquired memory B cell markers, and persisted indefinitely. Lineage tracing and IgH repertoire analyses revealed minimal interconversion between T-bet^- and T-bet⁺ MBCs, and parabionts showed differential tissue residency and recirculation properties. T-bet⁺ MBCs could be subdivided into recirculating T-bet^lo MBCs and spleen-resident T-bet^hi MBCs. Human MBCs displayed similar features. Conditional gene deletion studies revealed that T-bet expression in B cells was required for nearly all HA stalk-specific IgG2c antibodies and for durable neutralizing titers to influenza. Thus, T-bet expression distinguishes MBC subsets that have profoundly different homing, residency, and functional properties, and mediate distinct aspects of humoral immune memory.

Keywords: Age-associated B cells; B cell memory; BCR sequencing; Humoral immunity; T-bet(+) B cells; antibody; hemagglutinin stalk; immune repertoire profiling; influenza; tissue-resident.