GC-independent B cells contribute to durable humoral responses and protection in mice 2309338

Abstract Introduction In mice, memory B cell heterogeneity has been established but there are no distinguishing markers based on GC-origin. How GC-independent memory B cells differ functionally from GC-derived memory B cells remains unclear. Utilizing mice models could help us better understand the memory B cells of different origins. Methods Antigen experienced IgD-IgM- B cells were sorted from Bcl6fl/fl and Bcl6fl/flCD4Cre mice and analyzed using sc-RNA seq. Antigen-specific B cells were tracked up to 6 months post immunization. GC-dependent and independent resting B cells were transferred to Rag2ko mice with follicular helper T cells and the recipient mice were immunized with the same antigen. B cells from Tcrb ko and WT mice were phenotyped. Finally, Bcl6fl/fl and Bcl6fl/flCD4Cre mice were immunized and challenged with homologous and sub-heterotypic influenza viruses. Results B cells could be grouped into 4 GC-independent and 2 GC-dependent clusters. GC B cells (GL7+CD73+) and 1 resting B cell cluster were depleted in the absence of germinal centers. Non-GC resting B cells contribute to durable antigen specific B cell populations at least 6 months after immunization. After reencountering the same antigen, both GC and non-GC antigen-experienced resting B cell populations were reactivated and gave rise to germinal centers and GC-independent reactions in Rag2ko mice. GC-dependent resting B cells and only one population of GC-independent resting B cells, were depleted in the absence of T cell help. Non-GC B cell responses were protective to challenges with the lethal dose of homologous and heterologous influenza strains after immunization. Conclusion This study establishes the GC dependent and independent B cell populations contributing to memory B cells and mature plasma cells. Further studies are required to understand the interplay between GC-linked and non-GC derived memory B cells which could inform new vaccine strategies and treatment modalities in autoimmunity and cancer. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)