Dynamic regulation of Bcl6 in follicular helper CD4 T (Tfh) cells

Abstract

Our bodies are continuously exposed to various types of infectious pathogens. Vaccinations are the most cost effective way to protect our bodies against a variety of infectious microbes. The efficacy of most vaccines relies on protective antibody production and generation of memory B cells. These two key components develop mostly from B cells that participate in germinal center reactions. Recent efforts have highlighted the critical role of follicular helper CD4 T (Tfh) cells in the generation of germinal centers. Given that Bcl6 is a major transcription factor for Tfh differentiation, here we review recent developments in the understanding of signaling molecules that regulate Bcl6 expression in CD4 T cells, as a potential target for development of more efficacious vaccines.

Figure 1. Signaling pathways in regulation of Bcl6 expression of CD4 T cells

In antigen primed CD4 T cells, Bcl6 expression is regulated by various stimuli (i.e., ICOS, IL-6, IL-12, etc.). Signaling circuits are depicted with positive (arrows) and negative (bars) functions shown for signaling molecules that regulate Bcl6 expression or related processes. The solid lines indicate defined in the literature, whereas the dotted lines describe signaling pathways that are potentially involved in regulation of Bcl6 expression in CD4 T cells. Direct lines don’t imply direct binding.

Figure 2. Direct interaction of transcription factors with Bcl6 promoter regulatory region

Shown is the Bcl6 locus including −11 Kb promoter regulatory region. Transcription factors that bind to the Bcl6 promoter regulatory region are depicted. Arrows and bars indicate positive and negative roles of the transcription factors for Bcl6 expression, respectively. An unidentified signaling pathway is represented by a dotted line. Molecules in parentheses indicate transcription factors associated with Bcl6 expression regulation, but not confirmed to bind to Bcl6 gene.