Understanding the temporal requirement for T follicular helper cells for germinal center output of long-lived plasma cells and B memory cells.

Abstract

Abstract T follicular helper cells (Tfh) play a critical role in supplying help to B cells for the selection of high-affinity B cells in germinal centers (GC), that give rise to memory B cells (Bmem) and long-lived plasma cells (LLPCs). The products of the GC reaction appear to be temporally distinct, with Bmem cells produced early and LLPCs late. The temporal requirements for Tfh help are not well understood and we still do not know when and for how long this help is critical. In the total absence of help supplied by Tfh cells, both GCs and LLPCs are greatly diminished. Our previous work (Schrock, Leddon et al 2019, PNAS) suggested that sustained GC Tfh were critical for LLPC generation, but interestingly not for Bmem generation. We hypothesize that a temporal requirement for GC Tfh regulates LLPC versus Bmem GC output. To test this, we have established a number of models that allow for deletion of Tfh at different times post OVA/CFA immunization. To specifically target Tfh cells, CD4 iCRE Bcl6fl/fl mice were used for time-dependent deletion of Bcl6 upon tamoxifen administration at different stages of the GC reaction. Tfh and GC output are determined using multicolor Flow Cytometry panels, BM B cell Elispot for LLPCs and a Bmem Elispot. With these systems in place, we aim to pinpoint the temporal requirement for Tfh for both Bmem and LLPCs, speculating that timing of Tfh help will differ for these two arms of the GC response. Understanding this temporal requirement of Tfh help within the GC can not only help us to better design future vaccines that promote LLPCs, but also guide the development of drugs to modulate Tfh longevity in autoimmune disorders, where aberrant Tfh development or maintenance contribute to pathology.