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

Figure 3

Signaling pathway for ICOS costimulation in TFH cell differentiation. For TFH cell differentiation, ICOS-mediated recruitment of PI3K has a dual role in transcriptional regulation of genes. On the one hand, the activation of PI3K causes activation of Akt and subsequently inhibits the transcription factor Foxo1 function through phosphorylation-mediated cytosolic retention. The inhibition of Foxo1 upregulates Bcl-6 and downregulates KLF2, which both are crucial transcriptional regulators controlling the expression of TFH signature genes. On the other hand, the regulatory subunit p85α of PI3K can bind with the intracellular form of osteopontin (OPNi), whereafter OPNi migrates into the nucleus and binds to Bcl-6 which can protect Bcl-6 from ubiquitin-dependent degradation and regulate the expression of TFH signature genes.