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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 20; pp. 8152 - 8157
• Main Authors: Jia, Yi, Domenico, Joanne, Takeda, Katsuyuki, Han, Junyan, Wang, Meiqin, Armstrong, Michael, Reisdorph, Nichole, O'Connor, Brian P., Lucas, Joseph J., Gelfand, Erwin W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.05.2013; National Acad Sciences
• Subjects: Allergies; Animals; Asthma; Asthma - metabolism; Biochemistry; Biological Sciences; Bronchoalveolar Lavage Fluid; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - metabolism; Cell Differentiation; Cellular differentiation; Cholesterol Side-Chain Cleavage Enzyme - metabolism; Corticosteroids; Cytokines; Enzyme-Linked Immunosorbent Assay - methods; Enzymes; Gene expression; Hypersensitivity - metabolism; Inflammation; Interferon-gamma - metabolism; Interleukin-13 - metabolism; Interleukin-2 - pharmacology; Interleukin-4 - pharmacology; Lung Diseases - metabolism; Lungs; Mice; Mice, Inbred C57BL; Pregnenolone - pharmacology; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Rodents; T cell receptors; T lymphocytes; Transcription factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1216671110

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.