Human T Helper 9 Cells Rely on Peroxisome Proliferator-Activated Receptor-γ-Mediated Cystine Uptake to Prevent Lipid Peroxidation and Bioenergetic Failure

T helper 9 (Th9) cells are implicated in allergic skin inflammation and depend on the transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ) for full effector function. In this study, we uncovered a role for PPAR-γ in the amino acid metabolism of human Th9 cells. In in vitro-primed Th9 cells, PPAR-γ expression positively correlated with the expression of SLC7A8, which encodes LAT2, a transporter of large neutral Amino acids, including cystine. Inhibition of PPAR-γ led to a compensatory upregulation of SLC7A11, a subunit of the cystine-glutamine antiporter xCT, indicating a specific need for cystine uptake in Th9 cells. Indeed, Th9 cells were sensitive to cystine deprivation, which triggered lipid peroxidation and bioenergetic failure, resulting in a ferroptosis-like form of cell death. This outcome was further enforced by additional PPAR-γ inhibition. Finally, combined SLC7A11 and PPAR-γ inhibition depleted Th9 cells in ex vivo samples of acute allergic skin inflammation. Overall, our data suggest that human Th9 cells are dependent on uptake of exogenous cystine, which opens up promising therapeutic strategies for their inhibition or depletion in allergic skin inflammation.

Allergic skin inflammation; Amino acid metabolism; Atopic dermatitis (AD); Ferroptosis; Pathogenic Th2 cells (pTh2).