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

Introduction

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 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.

Importance of Tfh Cells

Aberrant activation of Tfh has also been implicated in many diseases, including:

• Multiple Sclerosis
• Diabetes
• 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.

Research Background

Through work over multiple years, the applicant has developed an understanding of Tfh as a highly dynamic population that requires 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.

Objectives of the Proposal

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:

1. How different qualities of memory B cells are formed
2. 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
3. A new understanding of the origin and quality of Tfh memory and associated GC T cell memory