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Sci Immunol. 2018 Dec 21;3(30). pii: eaau6759. doi: 10.1126/sciimmunol.aau6759.

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

Author information

1
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.
2
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA. jmarkle1@jhu.edu jean-laurent.casanova@rockefeller.edu.
3
Immunology Division, Garvan Institute of Medical Research and St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, New South Wales, Australia.
4
Center of Medical Immunology, Institute for Research in Biomedicine, Faculty of Biomedical Sciences, University of italian Switzerland (USI), Bellinzona, Switzerland.
5
Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
6
Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.
7
Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
8
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
9
Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Parkville, Victoria, Australia.
10
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
11
Paris Descartes University, Imagine Institute, Paris, France.
12
Innate Immunity Unit, Pasteur Institute, INSERM U1223, Paris, France.
13
Charles Bronfman Institute for Personalized Medicine, and the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
14
Human Evolutionary Genetics Unit, Department of Genomes and Genetics, Pasteur Institute, Paris, France.
15
Centre National de la Recherche Scientifique, UMR 2000, Paris, France.
16
Center of Bioinformatics, Biostatistics and Integrative Biology, Pasteur Institute, Paris, France.
17
Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
18
Institute for Clinical and Molecular Virology, University Erlangen-Nuremberg,Erlangen, Germany.
19
Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey.
20
Department of Pediatric Infectious Diseases, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.
21
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
22
Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
23
Centre for Molecular and Cellular Biology of Inflammation, King's College London, London, UK.
24
Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
25
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
26
EA4340 and Pathology Department, Ambroise Paré Hospital AP-HP, Versailles Saint-Quentin-en-Yvelines University, Paris-Saclay University, Boulogne, France.
27
Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands.
28
Study Center of Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France.
29
Institute of Microbiology, ETH Zurich, Switzerland.
30
Howard Hughes Medical Institute, New York, NY, USA.
31
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children AP-HP, Paris, France.

Abstract

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 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-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αβ T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-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-12Rβ2 or IL-23R deficiency, relative to IL-12Rβ1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rβ2-deficient than IL-12Rβ1-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-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ-dependent immunity to mycobacteria, both individually and much more so cooperatively.

PMID:
30578351
PMCID:
PMC6380365
DOI:
10.1126/sciimmunol.aau6759
[Indexed for MEDLINE]
Free PMC Article

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