title: IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations.
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 Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4(+)CCR6(+)CXCR3(+) αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.|Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Janet G
authors.initials: JG
authors.lastname: Markle
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.|St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Elissa K
authors.initials: EK
authors.lastname: Deenick
authors.affiliation: Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland.
authors.forename: Federico
authors.initials: F
authors.lastname: Mele
authors.affiliation: Department of Pediatrics, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Averbuch
authors.affiliation: Department of Immunology, School of Medicine, Universidad de Valparaíso, Santiago, Chile.|Department of Pediatrics, Padre Hurtado Hospital and Clinica Alemana, Santiago, Chile.
authors.forename: Macarena
authors.initials: M
authors.lastname: Lagos
authors.affiliation: Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alzahrani
authors.affiliation: Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Pediatrics, Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Muhsen
authors.affiliation: Department of Pediatrics, Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Rabih
authors.initials: R
authors.lastname: Halwani
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.|St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.|St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Wong
authors.affiliation: Institut Curie, INSERM U932, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Soudais
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Henderson
authors.affiliation: Caritas Baby Hospital, Post Office Box 11535, Jerusalem, Israel.
authors.forename: Hiyam
authors.initials: H
authors.lastname: Marzouqa
authors.affiliation: Caritas Baby Hospital, Post Office Box 11535, Jerusalem, Israel.
authors.forename: Jamal
authors.initials: J
authors.lastname: Shamma
authors.affiliation: Department of Immunology, School of Medicine, Universidad de Valparaíso, Santiago, Chile.|Department of Pediatrics, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Marcela
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Rubén
authors.initials: R
authors.lastname: Martinez-Barricarte
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Chizuru
authors.initials: C
authors.lastname: Okada
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.|St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.affiliation: Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Latorre
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Deswarte
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Jabot-Hanin
authors.affiliation: Trudeau Institute, Saranac Lake, NY 12983, USA.
authors.forename: Egidio
authors.initials: E
authors.lastname: Torrado
authors.affiliation: Trudeau Institute, Saranac Lake, NY 12983, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Fountain
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Aziz
authors.initials: A
authors.lastname: Belkadi
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Migaud
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Cecilia S Lindestam
authors.initials: CSL
authors.lastname: Arlehamn
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: Department of Radiology, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Breton
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.|Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.|Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Laboratoire Dynamique du Génome et Système Immunitaire, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.affiliation: Laboratoire Dynamique du Génome et Système Immunitaire, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.|Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France.
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.affiliation: Institute of Cellular Medicine, Newcastle University and Great North Children's Hospital, Newcastle upon Tyne NE4 6BE, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hambleton
authors.affiliation: Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
authors.affiliation: Department of Paediatric Allergy Immunology, University of Manchester, Royal Manchester Children's Hospital, Manchester, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.|Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.|Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France.|Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Institut Curie, INSERM U932, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lantz
authors.affiliation: Department of Pediatrics, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Engelhard
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.|Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Trudeau Institute, Saranac Lake, NY 12983, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Cooper
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.|Manton Center for Orphan Disease Research, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.|Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.|Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.affiliation: Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland.|Center of Medical Immunology, Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Sallusto
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.|Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.|Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.|St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.|Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France.|Paris Descartes University, Imagine Institute, Paris, France.|Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France.|Howard Hughes Medical Institute, New York, NY 10065, USA.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000483:Alleles; D000818:Animals; D002176:Candida albicans / Q000276:immunology*; D002178:Candidiasis, Chronic Mucocutaneous / Q000150:complications / Q000235:genetics* / Q000276:immunology; D002417:Cattle; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D006801:Humans; D007109:Immunity / Q000235:genetics*; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D051379:Mice; D009154:Mutation; D009163:Mycobacterium bovis / Q000276:immunology / Q000302:isolation & purification; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000302:isolation & purification; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics*; D010375:Pedigree; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000002:abnormalities / Q000276:immunology; D014380:Tuberculosis, Bovine / Q000235:genetics* / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology
chemical_list: D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma