title: Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A.
abstract: Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients' glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual's disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.
authors.affiliation: School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom; Inflammation and Immunotherapy Theme, National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital (National Health Service) Foundation Trust and University College London Institute of Ophthalmology, London EC1V 2PD, United Kingdom;
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Schewitz-Bowers
authors.affiliation: School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom; Inflammation and Immunotherapy Theme, National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital (National Health Service) Foundation Trust and University College London Institute of Ophthalmology, London EC1V 2PD, United Kingdom;
authors.forename: Philippa J P
authors.initials: PJ
authors.lastname: Lait
authors.affiliation: School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom; Inflammation and Immunotherapy Theme, National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital (National Health Service) Foundation Trust and University College London Institute of Ophthalmology, London EC1V 2PD, United Kingdom;
authors.forename: David A
authors.initials: DA
authors.lastname: Copland
authors.affiliation: Laboratory of Immunology, National Eye Institute.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Laboratory of Immunology, National Eye Institute.
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.affiliation: School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom; Bristol Eye Hospital, University Hospitals Bristol (National Health Service) Foundation Trust, Bristol BS1 3NU, United Kingdom; and.
authors.forename: Ashwin D
authors.initials: AD
authors.lastname: Dhanda
authors.affiliation: Laboratory of Immunology, National Eye Institute.
authors.forename: Barbara P
authors.initials: BP
authors.lastname: Vistica
authors.affiliation: School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom; Inflammation and Immunotherapy Theme, National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital (National Health Service) Foundation Trust and University College London Institute of Ophthalmology, London EC1V 2PD, United Kingdom;
authors.forename: Emily L
authors.initials: EL
authors.lastname: Williams
authors.affiliation: Laboratory of Immunology, National Eye Institute.
authors.forename: Baoying
authors.initials: B
authors.lastname: Liu
authors.affiliation: Laboratory of Immunology, National Eye Institute.
authors.forename: Shayma
authors.initials: S
authors.lastname: Jawad
authors.affiliation: Laboratory of Immunology, National Eye Institute.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Laboratory of Immunology, National Eye Institute.
authors.forename: William
authors.initials: W
authors.lastname: Tucker
authors.affiliation: Laboratory of Immunology, National Eye Institute.
authors.forename: Sima
authors.initials: S
authors.lastname: Hirani
authors.affiliation: Systems Biology Center, National Heart Lung Blood Institute, and.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Wakabayashi
authors.affiliation: Systems Biology Center, National Heart Lung Blood Institute, and.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Laboratory of Immunology, National Eye Institute.
authors.forename: Nida
authors.initials: N
authors.lastname: Sen
authors.affiliation: School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom;
authors.forename: Becky L
authors.initials: BL
authors.lastname: Conway-Campbell
authors.affiliation: Laboratory of Immunology, National Eye Institute.
authors.forename: Igal
authors.initials: I
authors.lastname: Gery
authors.affiliation: School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom; Inflammation and Immunotherapy Theme, National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital (National Health Service) Foundation Trust and University College London Institute of Ophthalmology, London EC1V 2PD, United Kingdom; Bristol Eye Hospital, University Hospitals Bristol (National Health Service) Foundation Trust, Bristol BS1 3NU, United Kingdom; and.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
authors.affiliation: Laboratory of Immunology, National Eye Institute, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Lai
authors.initials: L
authors.lastname: Wei
authors.affiliation: Laboratory of Immunology, National Eye Institute, Center for Human Immunology, Autoimmunity, and Inflammation, National Institutes of Health, Bethesda, MD 20892; nussenblattr@nei.nih.gov richard.lee@bristol.ac.uk.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Nussenblatt
authors.affiliation: School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol BS8 1TD, United Kingdom; Inflammation and Immunotherapy Theme, National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital (National Health Service) Foundation Trust and University College London Institute of Ophthalmology, London EC1V 2PD, United Kingdom; Bristol Eye Hospital, University Hospitals Bristol (National Health Service) Foundation Trust, Bristol BS1 3NU, United Kingdom; and nussenblattr@nei.nih.gov richard.lee@bristol.ac.uk.
authors.forename: Richard W J
authors.initials: RW
authors.lastname: Lee
mesh_terms: D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D019703:Calcineurin / Q000737:chemistry; D065095:Calcineurin Inhibitors / Q000737:chemistry; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016572:Cyclosporine / Q000737:chemistry*; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000737:chemistry*; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D013256:Steroids / Q000737:chemistry; D058504:Th17 Cells / Q000166:cytology*
chemical_list: D065095:Calcineurin Inhibitors; D005938:Glucocorticoids; D020381:Interleukin-17; D013256:Steroids; D007371:Interferon-gamma; D016572:Cyclosporine; D019703:Calcineurin
keywords: Th17; calcineurin inhibition; glucocorticoid; steroid resistance; uveitis