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: Satoshi Okada, Janet G Markle, Elissa K Deenick, Federico Mele, Dina Averbuch, Macarena Lagos, Mohammed Alzahrani, Saleh Al-Muhsen, Rabih Halwani, Cindy S Ma, Natalie Wong, Claire Soudais, Lauren A Henderson, Hiyam Marzouqa, Jamal Shamma, Marcela Gonzalez, Rubén Martinez-Barricarte, Chizuru Okada, Danielle T Avery, Daniela Latorre, Caroline Deswarte, Fabienne Jabot-Hanin, Egidio Torrado, Jeffrey Fountain, Aziz Belkadi, Yuval Itan, Bertrand Boisson, Mélanie Migaud, Cecilia S Lindestam Arlehamn, Alessandro Sette, Sylvain Breton, James McCluskey, Jamie Rossjohn, Jean-Pierre de Villartay, Despina Moshous, Sophie Hambleton, Sylvain Latour, Peter D Arkwright, Capucine Picard, Olivier Lantz, Dan Engelhard, Masao Kobayashi, Laurent Abel, Andrea M Cooper, Luigi D Notarangelo, Stéphanie Boisson-Dupuis, Anne Puel, Federica Sallusto, Jacinta Bustamante, Stuart G Tangye, Jean-Laurent Casanova
• Journal: Science (New York, N.Y.) (Science) Vol. 349 Issue 6248 Pg. 606-613 (Aug 07 2015) ISSN: 1095-9203 [Electronic] United States
• PMID: 26160376 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Interleukin-17
• Nuclear Receptor Subfamily 1, Group F, Member 3
• RORC protein, human
• Receptors, Antigen, T-Cell, alpha-beta
• Receptors, Antigen, T-Cell, gamma-delta
• Interferon-gamma

Topics

• Alleles
• Animals
• Candida albicans (immunology)
• Candidiasis, Chronic Mucocutaneous (complications, genetics, immunology)
• Cattle
• Child
• Child, Preschool
• DNA Mutational Analysis
• Exome (genetics)
• Female
• Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor
• Humans
• Immunity (genetics)
• Interferon-gamma (immunology)
• Interleukin-17 (immunology)
• Mice
• Mutation
• Mycobacterium bovis (immunology, isolation & purification)
• Mycobacterium tuberculosis (immunology, isolation & purification)
• Nuclear Receptor Subfamily 1, Group F, Member 3 (genetics)
• Pedigree
• Receptors, Antigen, T-Cell, alpha-beta (genetics, immunology)
• Receptors, Antigen, T-Cell, gamma-delta (genetics, immunology)
• Severe Combined Immunodeficiency (genetics)
• T-Lymphocytes (immunology)
• Thymus Gland (abnormalities, immunology)
• Tuberculosis, Bovine (genetics, immunology)
• Tuberculosis, Pulmonary (genetics, immunology)