Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8+T cell skewing in allergic lung disease

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Abstract
Allergic asthma is a heterogeneous inflammatory disorder of the airways characterized by chronic airway inflammation and airway hyperresponsiveness. Numbers of CD8+IL-13+ T cells are increased in asthmatics and during the development of experimental asthma in mice. In an atopic environment rich in IL-4, these CD8+ T cells mediate asthmatic responses, but the mechanisms regulating the conversion of CD8+ effector T cells from IFN-γ– to pathogenic IL-13–producing effector cells that contribute to an asthma phenotype have not been defined. Here, we show that cholesterol side-chain cleavage P450 enzyme, Cyp11a1, is a key regulator of CD8+ T-cell conversion. Expression of the gene, protein, and enzymatic activity of Cyp11a1 were markedly increased in CD8+ T cells differentiated in the presence of IL-2 plus IL-4 compared with cells differentiated in IL-2 alone. Inhibition of Cyp11a1 enzymatic activity with aminoglutethimide or reduction in the expression of Cyp11a1 using short hairpin RNA prevented the IL-4–induced conversion of IFN-γ– to IL-13–producing cells without affecting expression of the lineage-specific transcription factors T-box expressed in T cells (T-bet) or GATA binding protein 3 (GATA3). Adoptive transfer of aminoglutethimide-treated CD8+ T cells into sensitized and challenged CD8-deficient recipients failed to restore airway hyperresponsiveness and inflammation. We demonstrate that Cyp11a1 controls the phenotypic conversion of CD8+ T cells from IFN-γ to IL-13 production, linking steroidogenesis in CD8+ T cells, a nonclassical steroidogenic tissue, to a proallergic differentiation pathway.