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Sci Immunol. 2018 Dec 21;3(30). pii: eaau8714. doi: 10.1126/sciimmunol.aau8714.

Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant.

Author information

1
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA. stbo603@rockefeller.edu jean-laurent.casanova@rockefeller.edu.
2
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
3
Paris Descartes University, Imagine Institute, Paris, France.
4
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.
5
Cytokine Signaling Unit, Pasteur Institute, Paris, France.
6
INSERM U1221, Paris, France.
7
Human Evolutionary Genetics Unit, Pasteur Institute, Paris, France.
8
CNRS UMR2000, Paris, France.
9
Center of Bioinformatics, Biostatistics and Integrative Biology, Pasteur Institute, Paris, France.
10
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
11
Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden.
12
Department of Clinical Translational Research, Singapore General Hospital, Singapore, Singapore.
13
Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, USA.
14
St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.
15
Sidra Medicine, Doha, Qatar.
16
Department of Biochemistry, University of Montreal, Montreal, Quebec, Canada.
17
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
18
Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
19
Institute of Biochemical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
20
Laboratory of Microbiology, Clinical Laboratory Department School of Medicine, Pontifical Catholic University of Chile, Santiago, Chile.
21
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
22
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
23
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
24
Department of Pediatric Pulmonology, Necmettin Erbakan University, Meram Medical Faculty, Konya, Turkey.
25
Meram Faculty of Medicine, Department of Internal Medicine, Division of Allergy and Immunology, Necmettin Erbakan University, Konya, Turkey.
26
Jeffrey Modell Center for Diagnosis and Research in Primary Immunodeficiencies, Faculty of Medicine University of La Frontera, Temuco, Chile.
27
Department of Pediatrics, Federal University of São Paulo Medical School, São Paulo, Brazil.
28
Department of Immunology, Institute of Biomedical Sciences, and Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil.
29
National Institute of Genomic Medicine, Mexico City, Mexico.
30
Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
31
Department of Pneumology, Military Hospital Mohammed V, Rabat, Morocco.
32
Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany.
33
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
34
Department of Infectious Diseases, Medical School, Pontifical Catholic University of Chile, Santiago, Chile.
35
Department of Pediatrics, San Sebastián University, Santiago, Chile.
36
Department of Infectious Diseases and Pediatric Immunology, School of Medicine, Pontifical Catholic University of Chile, Santiago, Chile.
37
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT, USA.
38
Seattle Children's Research Institute and Department of Pediatrics, University of Washington, Seattle, WA, USA.
39
Department of Pediatric Immunology and Allergy, Necmettin Erbakan University, Meram Medical Faculty, Konya, Turkey.
40
Genetics Unit, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco.
41
Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France.
42
Beijing Genomics Institute BGI-Shenzhen, Shenzhen, China.
43
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
44
Howard Hughes Medical Institute, New York, NY, USA.

Abstract

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (P = 8.37 × 10-8; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.

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