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

Markle, Janet G.; Martínez-Barricarte, Rubén; Ma, Cindy S.; Deenick, Elissa K.; Ramírez-Alejo, Noé; Mele, Federico; Latorre, Daniela; Mahdaviani, Seyed Alireza; Aytekin, Caner; Mansouri, Davood; Bryant, Vanessa L.; Jabot-Hanin, Fabienne; Deswarte, Caroline; Nieto-Patlán, Alejandro; Surace, Laura; Kerner, Gaspard; Itan, Yuval; Jovic, Sandra; Avery, Danielle T.; Wong, Natalie; Rao, Geetha; Patin, Etienne; Okada, Satoshi; Bigio, Benedetta; Boisson, Bertrand; Rapaport, Franck; Seeleuthner, Yoann; Schmidt, Monika; Ikinciogullari, Aydan; Dogu, Figen; Tanir, Gonul; Tabarsi, Payam; Bloursaz, Mohammed Reza; Joseph, Julia K.; Heer, Avneet; Kong, Xiao-Fei; Migaud, Mélanie; Lazarov, Tomi; Geissmann, Frédéric; Fleckenstein, Bernhard; Lindestam Arlehamn, Cecilia; Sette, Alessandro; Puel, Anne; Emile, Jean-François; Vosse, Esther van de; Quintana-Murci, Lluis; Di Santo, James P.; Abel, Laurent; Boisson-Dupuis, Stéphanie; Bustamante, Jacinta; Tangye, Stuart G.; Sallusto, Federica; Casanova, Jean-Laurent

doi:10.1126/sciimmunol.aau6759

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Journal article

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

21.12.2018

Published in:

Science Immunology. - 2018, vol. 3, no. 30, p. eaau6759

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.

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