Development of Tbet- and CD11c-expressing B cells in a viral infection requires T follicular helper cells outside of germinal centers

Abstract

Tbet⁺CD11c⁺ B cells arise during type 1 pathogen challenge, aging, and autoimmunity in mice and humans. Here, we examined the developmental requirements of this B cell subset. In acute infection, T follicular helper (Tfh) cells, but not Th1 cells, drove Tbet⁺CD11c⁺ B cell generation through proximal delivery of help. Tbet⁺CD11c⁺ B cells developed prior to germinal center (GC) formation, exhibiting phenotypic and transcriptional profiles distinct from GC B cells. Fate tracking revealed that most Tbet⁺CD11c⁺ B cells developed independently of GC entry and cell-intrinsic Bcl6 expression. Tbet⁺CD11c⁺ and GC B cells exhibited minimal repertoire overlap, indicating distinct developmental pathways. As the infection resolved, Tbet⁺CD11c⁺ B cells localized to the marginal zone where splenic retention depended on integrins LFA-1 and VLA-4, forming a competitive memory subset that contributed to antibody production and secondary GC seeding upon rechallenge. Therefore, Tbet⁺CD11c⁺ B cells comprise a GC-independent memory subset capable of rapid and robust recall responses.

Keywords: Tbet(+)CD11c(+) B cells; Tfh cells; age-associated B cells; germinal center; humoral memory.