Inherited human ITK deficiency impairs IFN-? immunity and underlies tuberculosis

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dc.contributor.authorOgishi, Masato
dc.contributor.authorYang, Rui
dc.contributor.authorRodriguez, Remy
dc.contributor.authorGolec, Dominic P.
dc.contributor.authorMartin, Emmanuel
dc.contributor.authorPhilippot, Quentin
dc.contributor.authorBohlen, Jonathan
dc.date.accessioned2024-02-23T14:20:46Z
dc.date.available2024-02-23T14:20:46Z
dc.date.issued2022
dc.departmentNEÜen_US
dc.description.abstractInborn errors of IFN-gamma immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4(+) alpha beta T lymphocytopenia with a concomitant expansion of CD4(-)CD8(-) double-negative (DN) alpha beta and V delta 2(-) gamma delta T lymphocytes, both displaying a unique CD38(+)CD45RA(+)T-bet(+)EOMES(-) phenotype. Itk-deficient mice recapitulated an expansion of the gamma delta T and DN alpha beta T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients' T lymphocytes secrete small amounts of IFN-gamma in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients' total lymphocytes secrete small amounts of IFN-gamma, and CD4(+), CD8(+), DN alpha beta T, V delta 2(+) gamma delta T, and MAIT cells display impaired IFN-gamma production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-gamma-producing T cell subsets, thereby underlying TB.en_US
dc.description.sponsorshipEmpire State Stem Cell Fund for providing support through NYSDOH [RRID:SCR_017694]; NIH [C023046]; Harvard University Medical School; St. Giles Foundation; Institut National de la Sante et de la Recherche Medicale (INSERM), University of Paris, Sidra Medicine [SDR400048]; National Institute of Allergy and Infectious Diseases; National Center for Research Resources [R01AI095983, U19AI162568, U19AI142737]; National Center for Advancing Sciences of the National Institutes of Health [UL1TR001866]; French National Research Agency under the Investments for the Future program; Agence Nationale de Recherches sur le Sida et les Hepatites Virales project [ANR-10-IAHU-01, ANR-10-LABX-62-IBEID]; French Foundation for Medical Research [ECTZ170784-ANRS0073]; SCOR Corporate Foundation for Science [EQU201903007798]; David Rockefeller Graduate Program; Funai Foundation for Information Technology; Honjo International Scholarship Foundation; National Cancer Institute F99 Award [F99CA274708]; Immune Deficiency Foundation; Stony Wold-Herbert Fund; Ministerio de Ciencia Tecnologia e Innovacion MINCIENCIAS, Colombia [111574455633/CT 713-2016, 111584467551/CT 415-2020, CT 806-2018/046-2019]; Comite para el Desarrollo de la Investigacion, CODI-Universidad de Antioquia, Colombia; Care-for-Rare Foundation [CT 2017-16003]; Else Kroner-Fresenius Stiftung [160073]; German Federal Ministry of Education and Research [2017_A110]; Rockefeller University [01GM1910C]en_US
dc.description.sponsorshipWe would like to thank the patients, their relatives, and their physicians for participating in this study; Erin Williams, Dominick Papandrea, Yelena Nemirovskaya, Dana Liu, Mark Woollett, Lazaro Lorenzo, and Cecile Patissier for administrative assistance; Tatiana Kochetkov for technical assistance; the members of the laboratory for helpful discussions. We thank the Flow Cytometry Resource Center at The Rockefeller University (RRID:SCR_017694), and the Empire State Stem Cell Fund for providing support through NYSDOH Contract #C023046. We thank the NIH Tetramer Core Facility (NTCF) for providing the 5-OP-RU-loaded MR1 tetramer and PBS-57-loaded CD1d tetramer, which were developed jointly with Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie. We thank Stephen Elledge (Brigham and Women's Hospital, Harvard University Medical School, Boston, MA) for kindly providing the VirScan phage library.; The study was supported in part by a grant from the St. Giles Foundation, The Rockefeller University, Institut National de la Sante et de la Recherche Medicale (INSERM), University of Paris, Sidra Medicine (SDR400048), the National Institute of Allergy and Infectious Diseases (R01AI095983 and U19AI162568 to J.-L. Casanova and U19AI142737 to S. Boisson-Dupuis), the National Center for Research Resources, the National Center for Advancing Sciences of the National Institutes of Health (UL1TR001866), the French National Research Agency 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), Agence Nationale de Recherches sur le Sida et les Hepatites Virales project ECTZ170784-ANRS0073 (grant awarded to S. Boisson-Dupuis), the French Foundation for Medical Research (EQU201903007798), the SCOR Corporate Foundation for Science, and funding from the intramural program of the National Institute of Allergy and Infectious Diseases to P.L. Schwartzberg, D.P. Golec, and Z. Kaul. M. Ogishi was supported by the David Rockefeller Graduate Program, the New York Hideyo Noguchi Memorial Society, the Funai Foundation for Information Technology, the Honjo International Scholarship Foundation, and the National Cancer Institute F99 Award (F99CA274708). R. Yang was supported by the Immune Deficiency Foundation and the Stony Wold-Herbert Fund. A.A. Arias was supported by the Ministerio de Ciencia Tecnologia e Innovacion MINCIENCIAS, Colombia (111574455633/CT 713-2016 and 111584467551/CT 415-2020), Movilidad Academica ECOS-Nord/MINCIENCIAS, Colombia (CT 806-2018/046-2019) and Comite para el Desarrollo de la Investigacion, CODI-Universidad de Antioquia, Colombia (CT 2017-16003). F. Hauck was supported by the Care-for-Rare Foundation (160073), the Else Kroner-Fresenius Stiftung (2017_A110), and the German Federal Ministry of Education and Research (01GM1910C). Open Access funding provided by Rockefeller University.en_US
dc.identifier.doi10.1084/jem.20220484
dc.identifier.issn0022-1007
dc.identifier.issn1540-9538
dc.identifier.issue1en_US
dc.identifier.pmid36326697en_US
dc.identifier.scopus2-s2.0-85146519678en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1084/jem.20220484
dc.identifier.urihttps://hdl.handle.net/20.500.12452/13302
dc.identifier.volume220en_US
dc.identifier.wosWOS:001062493400001en_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.titleInherited human ITK deficiency impairs IFN-? immunity and underlies tuberculosisen_US
dc.typeArticleen_US

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