In the nick of time: TFH cells as architects of durable immunity 2626

Abstract Description T follicular helper (TFH) cells are essential in adaptive immunity, guiding germinal center B (GC B) cells to generate high-affinity, long-lasting antibodies. Through direct cell interactions (e.g., CD40) and cytokine release, TFH cells signals are delivered to GC B cells, supporting their survival and differentiation into memory B cells (Bmem) and long-lived plasma cells (LLPCs). We examined the critical timing of TFH help by temporal disruption of GC interactions through acute anti-CD40L treatment and an inducible TFH knockout model, using CD4Cre-ERT2BCL6fl/fl. Our results show that prolonged TFH -GC B cell interactions are vital for the generate LLPCs. Tfh disruption 3 weeks into the GC reaction, when Tfh numbers are declining, impairs subsequent LLPC numbers in the bone marrow. In contrast, only depletion of Tfh during the early GC response, but not at later stages, disrupted the generation of Bmem. Use of inducible S1PR2-TdT has enabled GC-derived Tfh tracking, to identify specific TFH signals that could help guide GC B cells toward LLPCs at these later stages. A better understanding of the temporal changes in TFH biology is required to assure optimal vaccine efficacy, and here we show by two different approaches that durable TFH responses are critical for establishing a robust, long-lasting LLPC response. Understanding these signals holds significant potential for the design of new vaccines that deliver enduring protection. Funding Sources NIH Research Project Grant Program (R01): AI136536 Topic Categories Vaccines and Immunotherapy (VAC)