Impaired IL-23-dependent induction of IFN-? underlies mycobacterial disease in patients with inherited TYK2 deficiency

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dc.contributor.authorOgishi, Masato
dc.contributor.authorAugusto Arias, Andres
dc.contributor.authorYang, Rui
dc.contributor.authorHan, Ji Eun
dc.contributor.authorZhang, Peng
dc.contributor.authorRinchai, Darawan
dc.contributor.authorHalpern, Joshua
dc.date.accessioned2024-02-23T14:20:46Z
dc.date.available2024-02-23T14:20:46Z
dc.date.issued2022
dc.departmentNEÜen_US
dc.description.abstractHuman cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-alpha/beta (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-gamma is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.en_US
dc.description.sponsorshipSt. Giles Foundation; Howard Hughes Medical Institute; Rockefeller University; Institut National de la Sante et de la Recherche M'edicale, University of Paris; Sidra Medicine; National Institute of Allergy and Infectious Diseases [R01AI095983, R01AI163029, U19AI142737, U19AI111143, U19AI162568]; National Center for Advancing Sciences of the National Institutes of Health [UL1TR001866]; Fisher Center for Alzheimer's Research Foundation; Meyer Foundation; JPB Foundation; French National Research Agency (ANR) under the Investments for the Future program [ANR-10-IAHU-01]; Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID, ANR-20-CE93-003, ANR-16-CE17-0005-01]; ANRS [ANRS-COV05, ECTZ170784]; European Union [824110]; French Foundation for Medical Research [EQU201903007798]; Square Foundation; Grandir-Fonds de solidarite pour l'enfance, Fondation du Souffle; Fondation du Souffle; REACTing-INSERM; SCOR Corporate Foundation for Science; National Medical Research Council Singapore; National University Health System, Singapore; Deutsche Forschungsgemeinschaft [EXC-21899, 390939984]; Bundesministerium fur Bildung und Forschung [GAIN 01GM1910A]; Ministerio de Ciencia Tecnologia e Innovacion MINCIENCIAS, Colombia [111574455633/CT 713-2016, 111584467551/CT 415-2020]; Movilidad Academica ECOS-Nord/MINCIENCIAS, Colombia [CT 8062018/046-2019]; Comite para el Desarrollo de la Investigacion, CODI -UdeA, Colombia [CT 2017-16003]; David Rockefeller Graduate Program; Funai Foundation for Information Technology; Honjo International Scholarship Foundation; New York Hideyo Noguchi Memorial Society; National Cancer Institute F99 Award [F99CA274708]; Immune Deficiency Foundation; Stony Wold-Herbert Fund; Australian Government Research Training Program Stipend Scholarship; Fulbright Future Scholarship; EMBOen_US
dc.description.sponsorshipThis study was supported in part by grants from the St. Giles Foundation, The Rockefeller University, Howard Hughes Medical Institute, Institut National de la Sant ' e et de la Recherche M ' edicale, University of Paris, Sidra Medicine, National Institute of Allergy and Infectious Diseases (R01AI095983 to J.-L. Casanova and J. Bustamante and R01AI163029 to J.-L. Casanova, U19AI142737 to S. Boisson-Dupuis, and U19AI111143 and U19AI162568 to J.-L. Casanova), the National Center for Advancing Sciences of the National Institutes of Health (UL1TR001866), the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the Investments for the Future program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), GENVIR (ANR-20-CE93-003 to L. Abel), GENMSMD (ANR-16-CE17-0005-01 for J. Bustamante), ANRS projects ANRS Nord-Sud (ANRS-COV05 to L. Abel), ANRS ECTZ170784 (to S. Boisson-Dupuis), the European Union's Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-Genomics), the French Foundation for Medical Research (EQU201903007798), the Square Foundation, Grandir-Fonds de solidarit ' e pour l'enfance, Fondation du Souffle, REACTing-INSERM, and the SCOR Corporate Foundation for Science. L. Chai was supported by the National Medical Research Council Singapore and the National University Health System, Singapore. S. Ehl was supported by the Deutsche Forschungsgemeinschaft (CIBSS, EXC-21899, Project ID 390939984) and the Bundesministerium fur Bildung und Forschung (GAIN 01GM1910A). A.A. Arias was supported by Ministerio de Ciencia Tecnolog ' ia e Innovacion MINCIENCIAS, Colombia (111574455633/CT 713-2016 and 111584467551/CT 415-2020); Movilidad Acad ' emica ECOS-Nord/MINCIENCIAS, Colombia (CT 8062018/046-2019); and Comit ' e para el Desarrollo de la Investigacion, CODI -UdeA, Colombia (CT 2017-16003). M. Ogishi was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology, the Honjo International Scholarship Foundation, the New York Hideyo Noguchi Memorial Society, and the National Cancer Institute F99 Award (F99CA274708). R. Yang was supported by the Immune Deficiency Foundation and the Stony Wold-Herbert Fund. N. Keating was funded by the Australian Government Research Training Program Stipend Scholarship and the Fulbright Future Scholarship. J. Bohlen was supported by fellowships from EMBO and Marie Pierre Curie. Open Access funding provided by Rockefeller University.en_US
dc.identifier.doi10.1084/jem.20220094
dc.identifier.issn0022-1007
dc.identifier.issn1540-9538
dc.identifier.issue10en_US
dc.identifier.pmid36094518en_US
dc.identifier.scopus2-s2.0-85136160433en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1084/jem.20220094
dc.identifier.urihttps://hdl.handle.net/20.500.12452/13300
dc.identifier.volume219en_US
dc.identifier.wosWOS:000892570400001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherRockefeller Univ Pressen_US
dc.relation.ispartofJournal Of Experimental Medicineen_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.titleImpaired IL-23-dependent induction of IFN-? underlies mycobacterial disease in patients with inherited TYK2 deficiencyen_US
dc.typeArticleen_US

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