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. 2023 Feb 3;14:1125503. doi: 10.3389/fimmu.2023.1125503

Figure 2.

Figure 2

Transcriptional control of Tfh cell differentiation. Tfh cell differentiation occurs in three main steps. The first step of Tfh cell differentiation is the interaction of naïve CD4+ T cells with DCs in the T cell zone. The expression of BCL-6, master TF of Tfh cells, is induced on multiple levels. Cytokines including IL-21, IL-6 and type I IFNs (IFN-a/b) drive Bcl-6 expression via the activation of STAT1/3. Besides, TFs LEF-1 and TCF-1 as well as the transcriptional co-activator BOB.1/OBF.1 together with TFs Oct-1/Oct-2 induce Bcl- 6 expression. BCL-6 in turn represses Blimp-1 and TFs favoring development into TH subpopulations. BCL-6 and the TF ASCL2 induce the expression of CXCR5 and suppresses CCR7 expression inducing migration of pre-Tfh cells to the B/T cell border. The second step of Tfh cell differentiation then occurs upon interaction of pre-Tfh cells with Ag-specific B cells in the B/T cell border. ICOS/ICOSL signaling represses the TF KLF2 thereby inhibiting migration back to the T cell zones. ICOS signaling also induces the TF c-MAF, which facilitates IL21 expression. The third step of differentiation occurs within GCs, where SLAM/SAP binding is required to stabilize B/T cell interactions. Here, pre-Tfh cells differentiate into Tfh cells, a further polarized state characterized by highest expression levels of BCL-6, CXCR5, PD-1, ICOS and BTLA. This figure was created with BioRender.com.