Tfh Control of the Germinal Center Response

Key to successful vaccination is the development of high affinity antibody production. T follicular helper (Tfh) cells play an essential role in regulating B cell affinity maturation in the germinal center of the lymph node. We are interested in the spatial cues that regulate Tfh germinal center retention and in understanding the temporal requirements for Tfh support of long-lived plasma cell generation.

Tfh numbers within the GC are a limiting factor in GC B cell selection. A balanced Tfh/GC association is critical for effective Ab-mediated responses: lack of Tfh positioning to the GC results in the collapse of the GC reaction while overt Tfh numbers leads to Ab-mediated autoimmunity. The signals that retain or maintain Tfh in the GC have been poorly defined. Such positioning/retention cues could represent important therapeutic targets to boost Tfh cells within the GCs to facilitate the generation of a robust protective Ab response to infection and vaccination, or to mitigate Tfh GC associations in Ab-mediated autoimmunity.

We have identified a new GC retention mechanism for Tfh; mediated through Tfh integrin V expression and the display of the RGD-containing integrin ligands by the GC FDC. Disruption of this pathway, by integrin V or 3 deficiency in T cells, had a major impact on the GC response with a striking loss of long-lived plasma cells (LLPC). These observations drive ongoing studies aimed at addressing fundamental questions of Tfh and GC dynamics including how Tfh dwell time in the GC impacts B cell affinity maturation.

Representative publications:
Meli et al 2016 Immunity
Schrock, Leddon et al 2019 PNAS