CD21 primes extrafollicular differentiation of autoreactive B cells in a TLR7-driven lupus model.

Abstract

The extrafollicular (EF) B cell differentiation pathway has emerged as a prominent source of autoantibody-secreting cells (ASCs) in systemic lupus erythematosus (SLE). CD21CD11cB cells are associated with aging, infection, and autoimmunity. They are key contributors to EF ASCs, yet their developmental trajectory and receptor programming are unclear. To study EF mechanics of autoreactive B cells, we adoptively transferred naïve B cell populations into 564Igi mice, which act as an autoreactive host enriched for autoantigens and T cell help. Time-resolved analyses revealed a Toll-like receptor 7 (TLR7)-dependent early escape of peripheral tolerance and a pre-ASC division program. We identified naïve-derived CD21cells as precursors of EF ASCs exhibiting elevated reliance on TLR7. Repertoire analysis delineated protoautoreactive B cell selection and receptor evolution toward self-reactivity. Continuous complement receptor 2 (CR2/CD21)-complement C3d and CD21-complement iC3b engagement triggered receptor down-regulation before proliferation. We reveal CD21 as an initiator of TLR7-dependent autoimmune EF proliferation and target for suppressing autoreactivity.