The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding

Abstract

How follicular helper T cells (TFH cells) differentiate to regulate B cell immunity is critical for effective protein vaccination. Here we define three transcription factor T-bet-expressing antigen-specific effector helper T cell subsets with distinguishable function, migratory properties and developmental programming in vivo. Expression of the transcriptional repressor Blimp-1 distinguished T zone ‘lymphoid’ effector helper T cells (CD62LhiCCR7hi) from CXCR5lo ‘emigrant’ effector helper T cells and CXCR5hi ‘resident’ TFH cells expressing the transcriptional repressor Bcl-6 (CD62LloCCR7lo). We then show by adoptive transfer and intact polyclonal responses that helper T cells with the highest specific binding of peptide-major histocompatibility complex class II and the most restricted T cell antigen receptor junctional diversity ‘preferentially’ developed into the antigen-specific effector TFH compartment. Our studies demonstrate a central function for differences in the binding strength of the T cell antigen receptor in the antigen-specific mechanisms that ‘program’ specialized effector TFH function in vivo.

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…The use of terms such as lineage, specification and master regulator are terms best aligned with developmental programmes, such as in Caenorhabditis elegans, in which the fate of each cell is predetermined and irreversible. Nature Reviews | Immunology T H 2 or T FH cell differentiation can dominate [55][56][57][58] . By contrast, weak TCR signalling, by transient or low-affinity TCR interactions, favours the induction of FOXP3 expression 59,60 .…”

IFN-γ–Producing CD4+ T Cells Promote Generation of Protective Germinal Center–Derived IgM+ B Cell Memory against Salmonella Typhi

“…The GC reaction that generates such B cell responses is regulated by a specific CD4 + T cell type known as T follicular helper (Tfh) cells, which can differentiate into various subtypes (e.g., Th1-like, Th2-like, Th17-like) (25,32). Tfh cell differentiation is initiated through contact with Ag-expressing dendritic cells (DCs) (33), leading to the rapid induction of the Tfh signature transcription factor BCL-6 (34). Hence the immediate Tfh differentiation program impinges on the subsequent T-B cell interaction including GC reaction and B cell memory formation.…”

A critical role of T follicular helper cells in human mucosal anti-influenza response that can be enhanced by immunological adjuvant CpG-DNA

“…Recently, identification of novel agent/adjuvants that promote T FH number or function thus to enhance antibody response has become an attractive vaccination strategy (Fazilleau et al, 2009;Spensieri et al, 2013).…”

“…T FH are typically identified by co-expression of CXCR5 together with other markers including ICOS, PD-1, BCL-6 (Breitfeld et al, 2000;Kim et al, 2001) (Choi et al, 2011;Fazilleau et al, 2009;Kerfoot et al, 2011;King, 2009;Laurent et al, 2010). A number of cytokines, particularly IL-21, are produced by T FH , and are considered to have a major role in T FH differentiation and function on B cell antibody response (King, 2009).…”