Recently, a subset of allergen-specific Th2 cells has been identified and termed “pathogenic” Th2 (pTh2) cells, based on their crucial role in mediating type-2-mediated immunopathology. pTh2 cells express high levels of the ligand-activated transcription factor peroxisome proliferator activated receptor gamma (PPAR-g). The functional role of PPAR-g for pTh2 cells, however, remains incompletely understood. Here, we analyzed the effect of PPAR-g inhibition on basic T cell functions such as IL-2- or T cell receptor (TCR)-induced proliferation in pTh2 cells isolated from peripheral blood. Strikingly, PPAR-g inhibition strongly reduced IL-2-induced proliferation, but not TCR-induced proliferation, suggesting specific control of cytokine signaling events by PPAR-g. To investigate the underlying mechanisms, we performed transcriptomic analysis of T cell clones treated with a chemical inhibitor (GW9962) of PPAR-g. Pathway analysis revealed that the IL-2 signaling pathway is affected by PPAR-g-inhibition, in line with our observation from the proliferation data. To assess the impact of PPAR-g inhibition on IL-2 signaling, we systematically measured its effect on phosphorylation of signal transducer and activator of transcription (STAT) molecules. Cells treated with GW9662 showed a significantly reduced phosphorylation of STAT3 and STAT5, while phosphorylation of STAT6 remained unaffected. Together, our findings suggest that PPAR-g is a positive regulator of the IL-2 signaling pathway in pTh2 cells. Since IL-2 is crucial for T cell proliferation and survival, PPAR-g might provide a selective advantage for pTh2 over conventional Th cells under conditions of limited IL-2 availability in the tissue. These findings further highlight the potential of PPAR-g as a therapeutic target in type 2 immunopathology.

ESDR005 - PPAR-gamma promotes proliferation of pathogenic Th2 cells through regulation of IL-2 signaling

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING