title: Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8+ T cell skewing in allergic lung disease.
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.
authors: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
authors: Yi
authors: Y
authors: Jia
authors: Joanne
authors: J
authors: Domenico
authors: Katsuyuki
authors: K
authors: Takeda
authors: Junyan
authors: J
authors: Han
authors: Meiqin
authors: M
authors: Wang
authors: Michael
authors: M
authors: Armstrong
authors: Nichole
authors: N
authors: Reisdorph
authors: Brian P
authors: BP
authors: O'Connor
authors: Joseph J
authors: JJ
authors: Lucas
authors: Erwin W
authors: EW
authors: Gelfand
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006967:Hypersensitivity / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008171:Lung Diseases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011284:Pregnenolone / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D018793:Interleukin-13; D007376:Interleukin-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015847:Interleukin-4; D011284:Pregnenolone; D007371:Interferon-gamma; D002786:Cholesterol Side-Chain Cleavage Enzyme
references: J Clin Endocrinol Metab. 2006 Aug;91(8):2821-6
references: 16705068
references: Nat Med. 2004 Aug;10(8):865-9
references: 15258576
references: J Immunol. 2011 Jun 1;186(11):6378-89
references: 21536806
references: J Steroid Biochem Mol Biol. 1995 Jun;53(1-6):355-60
references: 7626480
references: J Immunol. 2001 Sep 15;167(6):3057-63
references: 11544289
references: Endocrinology. 2001 Aug;142(8):3519-29
references: 11459798
references: J Allergy Clin Immunol. 2007 Jan;119(1):73-80
references: 17208587
references: J Allergy Clin Immunol. 2012 Jan;129(1):191-8.e1-4
references: 22079492
references: J Allergy Clin Immunol. 2009 Jan;123(1):249-57
references: 19130938
references: Mol Endocrinol. 1996 Sep;10(9):1084-94
references: 8885243
references: Annu Rev Immunol. 1989;7:145-73
references: 2523712
references: J Immunol. 2013 Apr 15;190(8):4056-65
references: 23509358
references: J Exp Med. 1994 Nov 1;180(5):1715-28
references: 7525836
references: Am J Respir Crit Care Med. 2005 Oct 1;172(7):837-41
references: 16085937
references: J Immunol. 2009 Jul 1;183(1):181-90
references: 19542429
references: Curr Opin Immunol. 2010 Jun;22(3):286-92
references: 20399089
references: Nat Med. 2012 May 04;18(5):673-83
references: 22561831
references: Mol Endocrinol. 2008 Apr;22(4):915-23
references: 18174359
references: J Immunol. 2007 Sep 1;179(5):2787-96
references: 17709492
references: J Immunol. 2004 Feb 15;172(4):2549-58
references: 14764728
references: Exp Biol Med (Maywood). 2009 Aug;234(8):880-907
references: 19491374
references: J Clin Endocrinol Metab. 2008 Mar;93(3):696-702
references: 18182448
references: J Immunol. 2005 Apr 15;174(8):4979-84
references: 15814727
references: Allergy. 2013;68(5):666-73
references: 23573812
references: J Exp Med. 1995 Mar 1;181(3):1229-33
references: 7869040
references: Curr Opin Immunol. 2009 Apr;21(2):153-60
references: 19375293
references: Blood. 2007 Sep 1;110(5):1570-7
references: 17525285
references: J Immunol. 1992 Mar 15;148(6):1652-6
references: 1347305
references: J Immunol. 2012 Feb 15;188(4):1734-41
references: 22250087
references: J Exp Med. 1996 Apr 1;183(4):1719-29
references: 8666929
references: J Allergy Clin Immunol. 2012 Jun;129(6):1611-20.e4
references: 22385629
references: J Clin Invest. 1994 Mar;93(3):944-50
references: 8132780
references: J Allergy Clin Immunol. 2008 Apr;121(4):864-71.e4
references: 18395551
references: J Allergy Clin Immunol. 2006 Mar;117(3):577-82
references: 16522456
references: FEBS J. 2006 Jul;273(13):2891-901
references: 16817851
references: Cell Immunol. 2000 Nov 25;206(1):7-15
references: 11161433
references: J Allergy Clin Immunol. 2001 Jun;107(6):945-57
references: 11398070
references: J Immunol. 2005 Dec 1;175(11):7103-7
references: 16301612
references: Nat Med. 2003 May;9(5):582-8
references: 12669034