Journal article
Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations
S Okada, JG Markle, EK Deenick, F Mele, D Averbuch, M Lagos, M Alzahrani, S Al-Muhsen, R Halwani, CS Ma, N Wong, C Soudais, LA Henderson, H Marzouqa, J Shamma, M Gonzalez, R Martinez-Barricarte, C Okada, DT Avery, D Latorre Show all
Science | Published : 2015
Abstract
Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Myc..
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Awarded by Canadian Institutes of Health Research
Funding Acknowledgements
We thank the patients and their families for their collaboration; both branches of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions and support; M. Hindiyeh for expert clinical care of the patients from Kindred A; G. C. Tsokos for providing the IL17A reporter luciferase plasmid; E. Van de Vosse for providing the pLZRS-IRES-DNGFR vector; D. Littman for helpful discussions; B. Fleckenstein and M. Schmidt for the generation of patient-derived T cell lines; and Y. Nemirovskaya, L. Amar, E. Anderson, M. Courat, and T. Nivare for administrative support. The data presented in the manuscript are tabulated in the main paper and in the supplementary materials. The sequence data are available in the Sequence Read Archive (www.ncbi.nlm.nih.gov/sra) with accession numbers SRS964935, SRS965039, SRS965040, and SRS965042. J.Mc. and The University of Melbourne filed Australian provisional patent application numbers 2014901185 and 2014901 that relate to ligands that bind MR1 and stimulate MAIT cells. The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the National Center for Research Resources and the National Center for Advancing Sciences, NIH (8UL1TR000043); the French National Research Agency (ANR) under the "Investments for the Future" program (grant ANR-10-IAHU-01), grant IFNGPHOX (13-ISV3-0001-01 to J.B.), and grant GENCMCD (11-BSV3-005-01 to A.P); Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID); the National Health and Medical Research Council (NHMRC) (to E.K.D., C.S.M., S.G.T, and J.Mc.); the Rockefeller University; INSERM; Universite Paris Descartes; the St. Giles Foundation; the National Institute of Allergy and Infectious Diseases (R37AI095983 to J.-L.C.); and the NIH (contract HHSN272200900044C to A.S.). S.O. was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (25713039 and 25670477), J.G.M. by the Canadian Institutes of Health Research, R.M.-B. by the European Molecular Biology Organization, Y.I. by the AXA Research Fund, L.A.H. by the Rheumatology Research Foundation's Scientist Development Award, and F.S. by grants from the European Research Council (323183 PREDICT) and the Swiss National Science Foundation (149475). The Institute for Research in Biomedicine and the Center of Medical Immunology are supported by the Helmut Horten Foundation. S.A.-M. is the bronchial asthma research chair of the Prince Naif Center for Immunology Research.