Follicular Helper CD4⁺ T Cells, Follicular Regulatory CD4⁺ T Cells, and Inducible Costimulator and Their Roles in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Figure 2

ICOS induces the differentiation of CD4⁺ T cell subsets. For Th1 cells, ICOS ligation upregulates transcription factors NFATc2 and T-bet and promotes IFN-γ production. For Th2 cells, ICOS engagement upregulates transcription factors NFATc1 and c-Maf and promotes GATA-3 transcription and the production of IL-4. Moreover, binding of ICOS to ICOSL promotes FOXP3 transcription, favoring NFAT binding to FOXP3 in Treg cells, and promotes IL-10, IL-35, and TGF-β secretion. In addition, ICOS-ICOSL interaction induces RORC2 and c-Maf expression and promotes IL-17 production in Th17 cells, whereas binding of ICOS to ICOSL induces Bcl-6 expression in TFH cells, leading to increased secretion of IL-21. What is more, ICOS ligation upregulates transcription factors FOXP3 and Bcl-6 and promotes IL-10 and TGF-β production in TFR cells.