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T helper 9 cells (TH9) are key drivers of allergic tissue inflammation. They are characterized by the expression of type 2 cytokines, such as IL-9 and IL-13, and the peroxisome proliferator-activated receptor gamma (PPAR-γ) transcription factor. However, the functional role of PPAR-γ in human TH9 cells remains unknown. Here, we demonstrate that PPAR-γ drives activation-induced glycolysis, which, in turn, specifically promotes the expression of IL-9, but not IL-13, in an mTORC1-dependent manner. In vitro and ex vivo experiments on skin samples of allergic contact dermatitis showed that the PPAR-γ-mTORC1-IL-9 pathway was active in TH9 cells in human skin inflammation. Additionally, we found that tissue glucose levels were dynamically regulated in acute allergic skin inflammation, suggesting that in situ glucose availability is linked to distinct immunological signals in vivo. Furthermore, paracrine IL-9 induced the lactate transporter MCT1 in IL-9R+ TH cells, where it increased aerobic glycolysis and proliferative capacity. Taken together, our findings delineate a hitherto unknown relationship between PPAR-γ-dependent glucose metabolism and the pathogenic effector function of human TH9 cells.Graphical abstract

T helper (TH) cells have evolved into distinct subsets that mediate specific immune responses to protect the host against a myriad of infectious and noninfectious challenges. However, if dysregulated, TH-cell subsets can cause inflammatory disease. Emerging evidence now suggests that human allergic disease is caused by a distinct subpopulation of pathogenic TH2 cells. Pathogenic TH2 cells from different type-2-driven diseases share a core phenotype and show overlapping functional attributes. The unique differentiation requirements, activating signals, and metabolic characteristics of pathogenic TH2 cells are just being discovered. A better knowledge of this particular TH2 cell population will enable the specific targeting of disease-driving pathways in allergy. In this review, we introduce a rational for classifying TH cells into distinct subsets, discuss the current knowledge on pathogenic TH2 cells, and summarize their involvement in allergic diseases.