miRNA-Dependent CD4⁺ T Cell Differentiation in the Pathogenesis of Multiple Sclerosis

Figure 1

Naive CD4⁺ cells are activated via antigen-presenting cell (APC) and differentiate into several subtypes, viz. Th1, Th2, Treg, or Th17, under the influence of specific cytokines. Differentiation of Th1 cells is stimulated by the presence of IL-12, which activates the signaling pathways associated with STAT proteins (STAT1 and STAT4) and T-bet transcription factor. Mature Th1 cells secrete proinflammatory cytokines: IL-2, IL-3, IFN-γ, and TNF-α. Th2 cells differentiate under the influence of IL-4 and STAT6, which activate GATA3 transcription factor and stimulate the production of cytokines, including IL-4, IL-5, IL-9, and IL-13. Treg cell differentiation is dependent on the presence of TGF-β, and the typical transcription factor expressed by Treg is FOXP3. TGF-β and IL-10 are also effector cytokines secreted by Treg cells. The presence of TGF-β and IL-6 stimulates the differentiation of Th17 cells through STAT3 signaling pathways, as well as transcription factors RORγt and RORα. In addition, Th17 differentiation can be induced by alternative pathways stimulated with IL-21 and IL-23 (activating STAT4). Major effector cytokines include IL-17, IL-17F, IL-21, and IL-22.