Cellular metabolism in Th9, Th17, and Treg cell differentiation

CD4+ helper T (Th) cell subsets play an essential role in the regulation of adaptive immunity. Th9, Th17, and regulatory T (Treg) cells require transforming growth factor-beta (TGF-β) for their differentiation; however, their respective functions are highly distinct. Recent studies have highlighted the critical role of cellular metabolism in initiating clonal expansion and facilitating the effector differentiation of Th cells. Upon antigen exposure, naïve CD4+ T cells undergo metabolic reprogramming to fulfill their bioenergetic and biosynthetic demands. This process involves a shift from fatty acid oxidation to glycolysis, which ensures a sufficient energy supply for activation and proliferation. Lipid metabolism plays a pivotal role in modulating the differentiation and function of Th17, Treg, and Th9 cells. This review explores the influence of metabolic pathways on key transcription factors, including retinoic-acid-related orphan receptor gamma t (RORγt) and SMADs, and emphasizes their regulatory roles in Th cell differentiation. Furthermore, it discusses emerging therapeutic strategies aimed at targeting cellular metabolism to address autoimmune and inflammatory diseases associated with these T-cell subsets.