PPARγ: a transfactor for Th-cell subsets

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear transcription factor that governs helper T cell (Th) immunometabolism and functional differentiation by regulating gene transcription, cellular metabolism, and cytokine microenvironment. In Th1 cells, PPARγ primarily regulates interferon-γ (IFN-γ) secretion. Within Th2 cells, it influences GATA-binding protein 3 (GATA3) expression and provides metabolic support for normal cellular functions. In Th17 cells, it inhibits RAR-related orphan receptor γt (RORγt) transcription and suppresses inflammatory signals, thereby alleviating Th17-mediated inflammatory responses. In Tregs, PPARγ aids in cell differentiation by activating forkhead box P3 (Foxp3) transcription and inducing metabolic reprogramming. In Th9 cells, PPARγ promotes the secretion of IL-9. Within Tfh cells, the deficiency of PPARγ leads to an increase in B cell leukemia/lymphoma 6 (Bcl-6) expression. Notably, PPARγ agonists and antagonists effectively preserve Th-cell homeostasis by targeting PPARγ-mediated metabolic and signaling pathways. This review summarizes PPARγ as a crucial transcription factor governing Th-cell responses and elucidates its underlying molecular mechanisms. Based on the evidence predominantly derived from animal models, it lays a foundation for translational research of PPARγ-targeted immunotherapy.