T cell subsets underlying the rise, fall and recall of the Germinal Center

ongoing

Follicular helper T cells (Tfh), through their cognate interactions with B cells, drive the Germinal Center (GC) reaction resulting in affinity matured memory B cells and Plasma cells, hallmarks of the adaptive immunity and underpinning our ability to counter pathogenic insults. For mounting a successful response against most pathogens, including the virus SarS-CoV-2 that has crippled most nations for over a year, Tfh cells are of central importance. Aberrant activation of Tfh has also been implicated in many diseases, including Multiple Sclerosis, Diabetes and Lymphoma. Understanding Tfh biology is essential for our understanding of the adaptive immune system and in our quest to develop better vaccines and therapeutic treatments, as it will enable us to modulate GC output. Through work over multiple years, the applicant has developed an understanding for Tfh as a highly dynamic population that require equally dynamic regulation. Understanding the true nature of Tfh, and of the T cell subsets that regulate Tfh, including the molecular mechanisms of regulation, will necessitate the combination of new tools with already existing state-of-the-art methods that is proposed herein. This will lead to a new understanding of how Tfh drive B cells throughout the GC, how they shape B cell responses, shedding light on unresolved issues such as how different quality of memory B cells is formed, and how the unappreciated phenomenon of GC termination, proceeds. Specifically this proposal will result in 1) A new definition of Tfh and of GC T cell regulatory subsets. 2) A mechanism for Foxp3+ T cell mediated regulation of GC B Cells and GC termination and 3) A new understanding of the origin and quality of Tfh memory and associated GC T cell memory.