Project Summary
T follicular helper (Tfh) cells are essential for germinal center (GC) responses and long-term
humoral immunity. However, the complex regulation that determines the differentiation of Tfh cells, in
particular, the initial CXCR5– versus CXCR5+ CD4+ T cell differentiation, the developmental
progression of CXCR5+CD4+ T cells to become GC-Tfh cells, and the generation of follicular helper-
like memory CD4+ T cells expressing CXCR5, are still not fully understood. Our proposal aims to fill in
these knowledge gaps with long-term goals to identify novel pathways underlying the differentiation of
CD4+ T cells.
In our preliminary studies, we have discovered a novel network engaging various
factors/pathways that fine-tunes CXCR5+ versus CXCR5– CD4+ T cell differentiation and regulates the
generation of cytotoxic CD4+ T cells in the early stage of CD4+ T cell response. By combining RNA-
seq, ATAC-seq, and single cell RNA-seq, our preliminary data also suggest that the PD-1+CXCR5+
pre-Tfh cells undergo substantial further differentiation to become PD-1hiCXCR5hi GC-Tfh cells.
Additionally, we have generated novel “fate-mapping” reporter mice that will allow us to track the
varied CXCR5– and CXCR5+ memory CD4+ T cells. Thus, in this application, we aim to dissect the
molecular underpinning of the early stage CXCR5+ versus CXCR5– CD4+ T cell differentiation as well
as to elucidate the mechanisms underlying the pre- to GC-Tfh differentiation and the generation of
diversified CD4+ T cell memory.
Our work will have a profound impact on the field of CD4+ T cell differentiation. The research
will not only shed new light on our understanding of the mechanisms underlying the multiple steps of
Tfh cell differentiation but also establish new model systems for memory CD4+ T cell studies. This
proposal has the potential to provide important knowledge on how to control both the humoral and the
cellular arms of the CD4+ T cell response for the treatment of infectious diseases and autoimmune
disorders and how to aid vaccine development for new pandemic threats.