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 comprise a distinct subset that arises during type 1 pathogen challenge, aging, and autoimmunity in mice and humans. Their developmental reliance upon T cell help and relationship to germinal center (GC) B cells are unclear. We examined Tbet+CD11c+ B cells induced by acute LCMV infections, finding that T follicular helper (Tfh), not T helper 1 (Th1), cells drove their generation prior to GC formation. Genetic fate-tracking and lineage tracing revealed that most Tbet+CD11c+ B cells were not GC-derived and developed independently of cell-intrinsic Bcl6 expression. They localized to the marginal zone where their splenic retention depended upon integrins LFA-1 and VLA-4. After viral clearance, Tbet+CD11c+ B cells formed an uncommon but competitive memory subset, contributing to antibody production and secondary GC seeding upon rechallenge. Therefore, Tbet+CD11c+ B cells are predominantly generated independently of the GC response, yet their development is dependent upon help delivered by Tfh cells.