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. 2018 Jul 16;9:1630. doi: 10.3389/fimmu.2018.01630

Figure 1.

Figure 1

Factors that positively regulate human T follicular helper (Tfh) cell differentiation. When interacting with antigen-presenting dendritic cells (DCs), naïve CD4+ T cells receive signals via three major receptor families: the T cell receptor (TCR, signal 1), receptors for co-stimulatory molecules (signal 2), and receptors for cytokines (signal 3). For signal 1, evidence in both mice and humans shows that strong TCR signals promote Tfh cell differentiation. For signal 2, in addition to CD28 signals which is essential for optimal T cell activation, signals via inducible co-stimulator and Ox40 promote human naïve CD4+ T cells to express multiple Tfh molecules. For Signal 3, among inflammatory cytokines that activated DCs produce, IL-12 and IL-23 play dominant roles for human naïve CD4+ T cells to express Tfh molecules. The effect of IL-12 and IL-23 is further enhanced by the co-presence of TGF-β family molecules, TGF-β and Activin A. Given that TGF-β and Activin A are often highly expressed in human inflamed tissues, the source of these cytokines might be both from interacting DCs and from microenvironment.