Transcriptional regulation of follicular T-helper (Tfh) cells

Abstract

T-follicular helper (Tfh) cells are a new subset of effector CD4(+) T cells that are specialized in helping B cells in the germinal center reaction. Tfh cells are distinct from other established CD4(+) T-cell lineages, Th1, Th2, Th17, and T-regulatory cells, in their gene expression profiles. Tfh cell differentiation results from a network of transcriptional regulation by a master transcriptional factor Bcl6 as well as IRF4, c-Maf, Batf, and STAT3/5. During Tfh cell ontogeny, increased CXCR5 expression directs activated T-cell migration to the follicles, and their interaction with B cells leads to Bcl6 upregulation, which helps establish effector and memory Tfh cell program. This review summarizes the recent progress in molecular mechanisms underlying Tfh differentiation and discusses the future perspectives for this important area of research.

Fig. 1. Transcriptional regulation of Tfh development

CD4⁺ T-cell priming by DCs leads to the generation of CXCR5⁺Bcl6^−/lo pre-Tfh cells with increasing activities of transcriptional factors including Batf, IRF4, and STAT3. Bcl6-independent CXCR5 expression drives a portion of T cells to migrate to the interfollicular region, where T-B interaction increases Bcl6 expression. Simultaneously, the suppression of transcriptional factor T-bet, GATA3, and ROR-γ are initiated, whereas IL-6/IL-21-triggered STAT3 signaling is increased. After entry into the follicle, the cognate interaction benefits B and T cells mutually and eventually completes Tfh and GC B-cell commitment. The fully committed Tfh (CXCR5^hiBcl6^hi) cells downregulate Th1, Th2, or Th17 programs.