Determining the role of T follicular helper cells in a multi-antigen germinal center model

Abstract

Abstract High-affinity antibodies produced by germinal center (GC) B cells are a crucial line of protection from viral infections. Canonically, T follicular helper (Tfh) cells provide essential helper signals to GC B cells through cognate Tfh-B cell interactions, thereby driving the iterative cycles of GC B cell selection. While our understanding of how Tfh cell help influences GC B cell selection in single-antigen GCs has significantly increased over the last few years, less is known in the setting of multi-antigen GCs, such as those induced by Influenza infection. Notably, during the course of Influenza infection major structural epitopes are accessible to B and T cells to various extents as either external or internal proteins. In theory, GC B cells can therefore receive help from different pools of Tfh populations, containing cells specific for the same (intramolecular) or another (linked help) antigen as the B cells. Recently, our lab developed LIPSTIC, an enzyme-mediated, proximity-dependent intercellular labeling technique, enabling us to directly record and quantify T cell help provided to B cells in vivo. Using LIPSTIC, we are studying how T cell help varies and is distributed among different viral protein-specific GC B cells and how competition for T cell help between different B cell clones shapes the antibody repertoire against flu. Furthermore, we aim to quantify the occurrence of intramolecular and linked T cell help as well as their contribution to GC selection.