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. 2016 Nov 23;7:520. doi: 10.3389/fimmu.2016.00520

Figure 1.

Figure 1

Follicular helper T cell differentiation and inhibition is multi-step, multifactorial, spatiotemporal. First step for naive CD4+ T cells to differentiate into Tfh involves antigen presentation by dendritic cells and CD28 co-stimulation leading to expression of LEF-1, TCF-1, ICOS and BCL-6. This early Tfh differentiation may be inhibited by expression of Blimp-1 FOCO-1, FOXp1, miR146a, Clul3, IL-2 and Roquin 1. The adjacent Treg cells either negatively regulate Tfh differentiation through CTLA-4 or promote the differentiation by reducing IL-2 at the vicinity of early Tfh cells. The expression of BCL-6 leads to the expression of CXCR5 and PD-1. The ICOS/ICOSL signaling downregulates KLF-2, which leads to upregulation of CXCR5 and downregulation of Blimp-1, T-bet, and CCR7. At this stage of Tfh differentiation, activin A also plays important role in downregulation of CCR7 and upregulation of CXCR5. CXCR5 upregulation leads to migration of these cells toward B cell follicle and interior of the germinal center. This step at T and B cell border is inhibited by IL-2 and Tfr through CTLA4. The migrated intermediate Tfh cells interacts with B cells through SAP/SLAM and signaling of which helps to stabilized Tfh generation which marks late event of Tfh differentiation and stable Tfh generation. Late stage of Tfh differentiation requires FOXO1 which at early stage is a negative regulator.