013 Cholesterol 25-hydroxylase expressing CD4+ T cell regulates skin inflammation

Excessive inflammation leaves unnecessary damage in the body and must be strictly regulated by multiple mechanisms. But the details have not been fully elucidated yet. The purpose of this study is to identify a new regulatory function of CD4 T cells. During Th subset differentiation, subset-determining cytokines always restrain differentiation to undesired subsets and authorize one particular subset to acquire specific functions. Therefore, when naïve T cell was stimulated with IL-27 and TGF-β that potently block differentiation to Th1, 2, 17 and iTreg, the stimulated T cell should obtain functions that have never been identified in those four subsets. Transcriptome analysis showed that one of the genes uniquely expressed in IL-27 and TGF-stimulated T cells was cholesterol 25-hydroxylase (Ch25h), an enzyme converting cholesterol to 25-hydroxycholesterol (25HC). qPCR and mass spectrometry revealed that IL-27-stimulated CD4 T cells expressed Ch25h in Stat1-dependent manner and secreted 25HC. Exogenous 25HC induced cell death in proliferating T cells in activation in vitro, but not in unstimulated ones. Transcriptome analysis of 25HC-treated T cells revealed that cholesterol synthesis was suppressed. Since exogenous cholesterol restored the cell death, T cells died of insufficient supply of cholesterol that is highly demanded in proliferating cells. To assess Ch25h roles in T cells in vivo, interface dermatitis model that Dsg3-specific (H1) T cells directly attack epidermis was employed. Strikingly, Ch25h-/-H1 T cells produced IFNg and IL-17a, and exacerbated the disease more notably than wild-type H1 T cells did. Collectively this study unveiled a new regulatory function of Ch25h+CD4 T cells that selectively targets activated T cells to prevent excessive inflammation.