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Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23

  • Markle, Janet G. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Martínez-Barricarte, Rubén St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Ma, Cindy S. Immunology Division, Garvan Institute of Medical Research and St Vincent’s Clinical School, Faculty of Medicine, University of NSW, Sydney, New South Wales, Australia
  • Deenick, Elissa K. Immunology Division, Garvan Institute of Medical Research and St Vincent’s Clinical School, Faculty of Medicine, University of NSW, Sydney, New South Wales, Australia
  • Ramírez-Alejo, Noé St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Mele, Federico Center of Medical Immunology, Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Latorre, Daniela Center of Medical Immunology, Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Mahdaviani, Seyed Alireza Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Aytekin, Caner Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey
  • Mansouri, Davood Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Bryant, Vanessa L. Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  • Jabot-Hanin, Fabienne Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
  • Deswarte, Caroline Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
  • Nieto-Patlán, Alejandro Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
  • Surace, Laura Innate Immunity Unit, Pasteur Institute, INSERM U1223, Paris, France
  • Kerner, Gaspard Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
  • Itan, Yuval St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Jovic, Sandra Center of Medical Immunology, Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Avery, Danielle T. Immunology Division, Garvan Institute of Medical Research and St Vincent’s Clinical School, Faculty of Medicine, University of NSW, Sydney, New South Wales, Australia
  • Wong, Natalie Immunology Division, Garvan Institute of Medical Research and St Vincent’s Clinical School, Faculty of Medicine, University of NSW, Sydney, New South Wales, Australia
  • Rao, Geetha Immunology Division, Garvan Institute of Medical Research and St Vincent’s Clinical School, Faculty of Medicine, University of NSW, Sydney, New South Wales, Australia
  • Patin, Etienne Human Evolutionary Genetics Unit, Department of Genomes and Genetics, Pasteur Institute, Paris, France
  • Okada, Satoshi Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan
  • Bigio, Benedetta St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Boisson, Bertrand St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Rapaport, Franck St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Seeleuthner, Yoann Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
  • Schmidt, Monika Institute for Clinical and Molecular Virology, University Erlangen-Nuremberg, Erlangen, Germany
  • Ikinciogullari, Aydan Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey
  • Dogu, Figen Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey
  • Tanir, Gonul Department of Pediatric Infectious Diseases, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey
  • Tabarsi, Payam Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Bloursaz, Mohammed Reza Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Joseph, Julia K. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Heer, Avneet St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Kong, Xiao-Fei St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Migaud, Mélanie Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
  • Lazarov, Tomi Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Geissmann, Frédéric Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Fleckenstein, Bernhard Institute for Clinical and Molecular Virology, University Erlangen-Nuremberg, Erlangen, Germany
  • Lindestam Arlehamn, Cecilia Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
  • Sette, Alessandro Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
  • Puel, Anne St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Emile, Jean-François EA4340 and Pathology Department, Ambroise Paré Hospital AP-HP, Versailles Saint-Quentin-en-Yvelines University, Paris-Saclay University, Boulogne, France
  • Vosse, Esther van de Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands
  • Quintana-Murci, Lluis Human Evolutionary Genetics Unit, Department of Genomes and Genetics, Pasteur Institute, Paris, France
  • Di Santo, James P. Innate Immunity Unit, Pasteur Institute, INSERM U1223, Paris, France
  • Abel, Laurent St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Boisson-Dupuis, Stéphanie St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Bustamante, Jacinta St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
  • Tangye, Stuart G. Immunology Division, Garvan Institute of Medical Research and St Vincent’s Clinical School, Faculty of Medicine, University of NSW, Sydney, New South Wales, Australia
  • Sallusto, Federica Center of Medical Immunology, Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Casanova, Jean-Laurent St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
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    21.12.2018
Published in:
  • Science Immunology. - 2018, vol. 3, no. 30, p. eaau6759
Immune system
Genetic variation
Mycobacterium infections
Sistema immunitario
Genetica medica
Mutazioni
Infezioni
English Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rß1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL- 12–dependent IFN-? immunity and IL-23–dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL- 12Rß2 or IL-23R deficiency, lacking responses to IL-12 or IL- 23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that aß T, ?d T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-? in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-? in response to IL-23. We also show that the development of IFN-?–producing CD4+ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RA-CCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rß2 or IL-23R deficiency, relative to IL-12Rß1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R– and IL-12Rß2–deficient than IL-12Rß1–deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-?, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-?–dependent immunity to mycobacteria, both individually and much more so cooperatively.
Language
  • English
Classification
Pathology, clinical medicine
License
License undefined
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Persistent URL
https://n2t.net/ark:/12658/srd1318770
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