Innate receptors CD21 and TLR7 attune tissue dynamics and drive extrafollicular evolution of autoreactive B cells

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B595
Abstract ID: 4607

Presenting Author:
Danni Y Zhu , Graduate student at Harvard Med. Sch., Boston Children's Hosp., Harvard Med. Sch.

Abstract:

In systemic lupus erythematosus (SLE), recent findings revise the traditional view of the germinal center being a primary source of pathogenic B cells and highlight the extrafollicular (EF) pathway as a prominent source of autoantibody-secreting cells (ASCs). CD21^loCD11c⁺ B cells, identified in mice as “age-associated B cells” and in human as “DN2 cells”, are potential contributors to autoreactive EF ASCs but have an obscure developmental trajectory. To study EF autoreactive B cell dynamics in vivo, we adoptively transferred WT and gene knockout B cells into the 564Igi mice – an autoreactive host which functions as an inflammatory “environment” enriched with autoantigens and T cell help. Time-stamped analyses of donor cells revealed TLR7 dependence in escape of tolerance and sustaining a division program that precedes ASC development. Follicular B cell derived CD21^lo cells were proposed precursors of EF ASCs due to their elevated TLR7 sensitivity and proliferative nature. Paradoxically, blocking receptor function reversed CD21 loss and effector cell generation, portraying CD21 as a differentiation initiator and a potential target for autoreactive B cell suppression. BCR repertoire analysis further delineated proto-autoreactive B cell developmental trajectories and clonal evolution toward self-reactivity. This work elucidates receptor and clonal dynamics in extrafollicular development of autoreactive B cells, laying groundwork for in vivo mechanistic studies in SLE.