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

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dc.contributor.authorBoisson-Dupuis, Stephanie
dc.contributor.authorRamirez-Alejo, Noe
dc.contributor.authorLi, Zhi
dc.contributor.authorPatin, Etienne
dc.contributor.authorRao, Geetha
dc.contributor.authorKerner, Gaspard
dc.contributor.authorLim, Che Kang
dc.date.accessioned2024-02-23T14:26:09Z
dc.date.available2024-02-23T14:26:09Z
dc.date.issued2018
dc.departmentNEÜen_US
dc.description.abstractInherited IL-12R beta 1 and TYK2 deficiencies impair both IL-12- and IL-23 -dependent IFN-gamma 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 x 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-alpha, IL-10, or even IL-12, which, like IL-23, induces IFN-gamma 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-gamma by IL-23 and is a common monogenic etiology of tuberculosis.en_US
dc.description.sponsorshipFrench National Agency for Research (ANR) [ANR-10-IAHU-01]; TBPATHGEN project [ANR-14-CE14-0007-01]; GENMSMD project [ANR-16-CE17-0005-01]; Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]; European Research Council (ERC) [ERC-2010-AdG-268777]; SCOR Corporate Foundation for Science; St. Giles Foundation; National Center for Research Resources; National Center for Advancing Sciences (NCATS), NIH [UL1TR001866]; National Institute of Allergy and Infectious Diseases (NIAID) [5R01AI089970, 5R37AI095983, 5U01AI088685, 5U19AI111143]; Rockefeller University; Fondation de la Recherche Medicale [DEQ20170336741]; National Health and Medical Research Council of Australia; Office of Health and Medical Research of the Government of New South Wales (Australia); Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) [1171570]; Fundacao de Amparo a Pesquisa do Estado e de Sao Paulo (Fapesp); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Consejo Nacional de Ciencia y Tecnologia (CONACYT) [264011]; Stony Wold-Herbert Fund; CNRS; Charles H. Revson Senior Fellowship in Biomedical Sciences; NIAID [K99AI27932]; Damon Runyon Cancer Research Foundation [PST-03-15]; Jeffrey Modell Foundation; Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH [T32GM007739]; National Human Genome Research Institute [UM1HG006504]; National Heart, Lung, and Blood Institute; [SRC2017]en_US
dc.description.sponsorshipThe Laboratory of Human Genetics of Infectious Diseases was supported, in part, by grants from the French National Agency for Research (ANR) under the Investissement d'avenir program (grant no. ANR-10-IAHU-01), the TBPATHGEN project (grant no. ANR-14-CE14-0007-01), the GENMSMD project (grant no. ANR-16-CE17-0005-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (grant no. ANR-10-LABX-62-IBEID), the European Research Council (ERC; grant no. ERC-2010-AdG-268777), the SCOR Corporate Foundation for Science, the St. Giles Foundation, the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), NIH (grant no. UL1TR001866), the National Institute of Allergy and Infectious Diseases (NIAID) (grant nos. 5R01AI089970, 5R37AI095983, 5U01AI088685, and 5U19AI111143), and The Rockefeller University. Work at the Cytokine Signaling Unit was supported, in part, by a grant from Fondation de la Recherche Medicale to S. Pellegrini (grant no. DEQ20170336741). J.B. was supported by Support of Clinical Research (grant no. SRC2017). C.S.M. and S.G.T. were supported by fellowships and grants from the National Health and Medical Research Council of Australia and the Office of Health and Medical Research of the Government of New South Wales (Australia). M.E.B. was supported by Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT; grant no. 1171570) A.C.-N. was supported by Fundacao de Amparo a Pesquisa do Estado e de Sao Paulo (Fapesp) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). N.R.-A. was supported by fellowships from Consejo Nacional de Ciencia y Tecnologia (CONACYT; grant no. 264011) and the Stony Wold-Herbert Fund. Z.L. was supported by the CNRS. J. Markle was supported by the Charles H. Revson Senior Fellowship in Biomedical Sciences and NIAID grant K99AI27932. C.C.J. was the Damon Runyon-Richard Lumsden Foundation Physician Scientist supported by the Damon Runyon Cancer Research Foundation (PST-03-15). H.D.O. was supported by the Jeffrey Modell Foundation. N.H. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH under award no. T32GM007739 to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program. The content of this study is the sole responsibility of the authors and does not necessarily represent the official views of the NIH. The Yale Center for Mendelian Genomics (UM1HG006504) is funded by the National Human Genome Research Institute. Funds were also provided by the National Heart, Lung, and Blood Institute. The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination.en_US
dc.identifier.doi10.1126/sciimmunol.aau8714
dc.identifier.issn2470-9468
dc.identifier.issue30en_US
dc.identifier.pmid30578352en_US
dc.identifier.scopus2-s2.0-85058915562en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1126/sciimmunol.aau8714
dc.identifier.urihttps://hdl.handle.net/20.500.12452/14069
dc.identifier.volume3en_US
dc.identifier.wosWOS:000455005400004en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherAmer Assoc Advancement Scienceen_US
dc.relation.ispartofScience Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleTuberculosis and impaired IL-23-dependent IFN-? immunity in humans homozygous for a common TYK2 missense varianten_US
dc.typeArticleen_US

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