Human IL-23 is essential for IFN-γ–dependent immunity to mycobacteria

Quentin Philippot; Masato Ogishi; Jonathan Bohlen; Julia Puchan; Andrés Augusto Arias; Tina Nguyen; Marta Martin-Fernandez; Clement Conil; Darawan Rinchai; Mana Momenilandi; Seyed Alireza Mahdaviani; Mohammad Keramatipour; Jérémie Rosain; Rui Yang; Taushif Khan; Anna Lena Neehus; Marie Materna; Ji Eun Han; Jessica Peel; Federico Mele; Marc Weisshaar; Sandra Jovic; Paul Bastard; Romain Lévy; Tom Le Voyer; Peng Zhang; Majistor Raj Luxman Maglorius Renkilaraj; Carlos A. Arango-Franco; Simon Pelham; Yoann Seeleuthner; Mathieu Pochon; Manar Mahmoud Ahmad Ata; Fatima Al Ali; Mélanie Migaud; Camille Soudée; Tatiana Kochetkov; Anne Molitor; Raphael Carapito; Seiamak Bahram; Bertrand Boisson; Claire Fieschi; Davood Mansouri; Nico Marr; Satoshi Okada; Mohammad Shahrooei; Nima Parvaneh; Zahra Chavoshzadeh; Aurélie Cobat; Dusan Bogunovic; Laurent Abel; Stuart G. Tangye; Cindy S. Ma; Vivien Béziat; Federica Sallusto; Stéphanie Boisson-Dupuis; Jacinta Bustamante; Jean Laurent Casanova; Anne Puel

doi:10.1126/sciimmunol.abq5204

Human IL-23 is essential for IFN-γ–dependent immunity to mycobacteria

Quentin Philippot, Masato Ogishi, Jonathan Bohlen, Julia Puchan, Andrés Augusto Arias, Tina Nguyen, Marta Martin-Fernandez, Clement Conil, Darawan Rinchai, Mana Momenilandi, Seyed Alireza Mahdaviani, Mohammad Keramatipour, Jérémie Rosain, Rui Yang, Taushif Khan, Anna Lena Neehus, Marie Materna, Ji Eun Han, Jessica Peel, Federico MeleMarc Weisshaar, Sandra Jovic, Paul Bastard, Romain Lévy, Tom Le Voyer, Peng Zhang, Majistor Raj Luxman Maglorius Renkilaraj, Carlos A. Arango-Franco, Simon Pelham, Yoann Seeleuthner, Mathieu Pochon, Manar Mahmoud Ahmad Ata, Fatima Al Ali, Mélanie Migaud, Camille Soudée, Tatiana Kochetkov, Anne Molitor, Raphael Carapito, Seiamak Bahram, Bertrand Boisson, Claire Fieschi, Davood Mansouri, Nico Marr, Satoshi Okada, Mohammad Shahrooei, Nima Parvaneh, Zahra Chavoshzadeh, Aurélie Cobat, Dusan Bogunovic, Laurent Abel, Stuart G. Tangye, Cindy S. Ma, Vivien Béziat, Federica Sallusto, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Jean Laurent Casanova, Anne Puel

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Patients with autosomal recessive (AR) IL-12p40 or IL-12Rβ1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium-inducible IFN-γ immunity in both Vδ2⁺ γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F–dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ–dependent immunity to Mycobacterium in at least two lymphocyte subsets.

Original language	English
Article number	eabq5204
Journal	Science immunology
Volume	8
Issue number	80
DOIs	https://doi.org/10.1126/sciimmunol.abq5204
State	Published - Feb 2023

Access to Document

10.1126/sciimmunol.abq5204

Cite this

Philippot, Q., Ogishi, M., Bohlen, J., Puchan, J., Arias, A. A., Nguyen, T., Martin-Fernandez, M., Conil, C., Rinchai, D., Momenilandi, M., Mahdaviani, S. A., Keramatipour, M., Rosain, J., Yang, R., Khan, T., Neehus, A. L., Materna, M., Han, J. E., Peel, J., ... Puel, A. (2023). Human IL-23 is essential for IFN-γ–dependent immunity to mycobacteria. Science immunology, 8(80), [eabq5204]. https://doi.org/10.1126/sciimmunol.abq5204

@article{8106aca56c7041949871dcb8a20ae9c1,

title = "Human IL-23 is essential for IFN-γ–dependent immunity to mycobacteria",

abstract = "Patients with autosomal recessive (AR) IL-12p40 or IL-12Rβ1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium-inducible IFN-γ immunity in both Vδ2+ γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F–dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ–dependent immunity to Mycobacterium in at least two lymphocyte subsets.",

author = "Quentin Philippot and Masato Ogishi and Jonathan Bohlen and Julia Puchan and Arias, {Andr{\'e}s Augusto} and Tina Nguyen and Marta Martin-Fernandez and Clement Conil and Darawan Rinchai and Mana Momenilandi and Mahdaviani, {Seyed Alireza} and Mohammad Keramatipour and J{\'e}r{\'e}mie Rosain and Rui Yang and Taushif Khan and Neehus, {Anna Lena} and Marie Materna and Han, {Ji Eun} and Jessica Peel and Federico Mele and Marc Weisshaar and Sandra Jovic and Paul Bastard and Romain L{\'e}vy and {Le Voyer}, Tom and Peng Zhang and Renkilaraj, {Majistor Raj Luxman Maglorius} and Arango-Franco, {Carlos A.} and Simon Pelham and Yoann Seeleuthner and Mathieu Pochon and Ata, {Manar Mahmoud Ahmad} and {Al Ali}, Fatima and M{\'e}lanie Migaud and Camille Soud{\'e}e and Tatiana Kochetkov and Anne Molitor and Raphael Carapito and Seiamak Bahram and Bertrand Boisson and Claire Fieschi and Davood Mansouri and Nico Marr and Satoshi Okada and Mohammad Shahrooei and Nima Parvaneh and Zahra Chavoshzadeh and Aur{\'e}lie Cobat and Dusan Bogunovic and Laurent Abel and Tangye, {Stuart G.} and Ma, {Cindy S.} and Vivien B{\'e}ziat and Federica Sallusto and St{\'e}phanie Boisson-Dupuis and Jacinta Bustamante and Casanova, {Jean Laurent} and Anne Puel",

note = "Funding Information: Acknowledgments:W ethankthepatientsandtheirfamiliesforplacingtheirtrustinus.W e thankthemembersofbothbranchesoftheLaboratoryofHumanGeneticsofInfectious Diseases.W ethankJ.MarkleandR.Martinez-Barricarteforhelpfuldiscussions.W ethank Y .Nemiro vskay a, M.W oollett, D.Liu,S.Boucherit,E.Williams,C.Rivalain,M.Chrabieh,and L. Lorenzo for administrative assistance. W e thank S. Elledge (Brigham and W omen {\textquoteright}s Hospital andHarvardMedicalSchool)forpro viding theVirScanphagelibraryusedinthisstudy.W e thanktheNIHT etr amerCoreFa cility (NTCF)forprovidingthe5-OP-RU–loadedMR1tetramer, whichwasdevelopedjointlywithJ.McCluskey ,J.Rossjohn,andD.Fairlie.Thefollowingreagent wasobtainedthroughBEIResources,NIAID,NIH:M.tuberculosis,strainH37Rv,whole-celllysate, NR-14822.Funding:TheHGMIlaboratorywasfunded,inpart,bytheNationalInstituteof AllergyandInfectiousDiseases(NIAID),NIH[grantnos.R01AI095983(toJ.-L.C.and J.Bustamante),R01AI127564(toJ.-L.C.andA.P .), andU19AI162568(toJ.-L.C.)];theNational CenterforResearchResourcesandtheNationalCenterforAdvancingSciences,NIH;the RockefellerUniversity;St.GilesFoundation;InstitutNationaldelaSant{\'e}etdelaRecherche M{\'e}dicale(INSERM);ParisCit{\'e}University;theIntegrativeBiologyofEmergingInfectious DiseasesLaboratoryofExcellence(ANR-10-LABX-62-IBEID);theFrenchNationalResearch Agency(ANR)underthe“InvestmentsfortheFuture”program(ANR-10-IAHU-01),CrossLab Imagine Grant (The inborn errors of the keratinocyte-leukocyte cross-talk in humans to A.P .), ANR-GENMSMD(ANR-16-CE17-0005-01toJ.Bustamante),ANRFNSL Th-MSMD-CMCD (grant no.ANR-18-CE93-0008-01toF .S. andA.P .), andANRSprojectECTZ170784-ANRS0073andANRS projectECTZ170784-ANRS0073toS.B.-D.;theFrenchFoundationforMedicalResearch(FRM; EQU201903007798); the European Union{\textquoteright}s Horizon 2020 research and innovation program undergrantagreementno.824110(EASI-genomics);theSquareFoundation,Grandir-Fondsde solidarit{\'e} pour l{\textquoteright}enfance; the SCOR Corporate Foundation for Science; and the Swiss National ScienceFoundation(no.310030L_182728toF .S.). Q.P .wassupportedbytheAssistance PubliqueH{\^o}pitauxdeParis(Ann{\'e}eRecherche)andissupportedbytheMD-PhDprogramof INSERM (Ecole de l{\textquoteright}INSERM Liliane Bettencourt). J. Bohlen is supported by the EMBO fellowship program.J.R.wassupportedbytheINSERMPhDprogramfordoctorsofpharmacy(Poste d{\textquoteright}accueil INSERM). J.R. and T .L.V . are supported by the Bettencourt-Schueller Foundation and theMD-PhDprogramoftheImagineInstitute.A.-L.N.issupportedbytheBettencourtSchueller FoundationandtheInternationalPhDprogr am oftheImagineInstitute.M.O.issupportedby theDavidRockefellerGraduateProgram,theNewYorkHideyoNoguchiMemorialSociety (HNMS),theFunaiFoundationforInformationT echnology (FFIT),theHonjoInternational ScholarshipFoundation(HISF),andtheNationalCancerInstitute(NCI)F99A ward (F99CA274708).A.A.A.andC.A.A.-F .aresupportedbyMinisteriodeCienciaT ecnolog{\'i}a e Innovaci{\'o}nMINCIENCIAS,Colombia(111574455633/CT713-2016and111584467551/CT415-2020);theMovilidadAcad{\'e}micaECOS-Nord/MINCIENCIAS,Colombia(CT806-2018/046-2019); andtheComit{\'e}paraelDesarrollodelaInvestigaci{\'o}n,CODI-UdeA,Colombia(CT2017-16003). R.Y .wassupportedbytheImmuneDeficiencyFoundationandtheStonyW old-Herbert Fund. N.M.wassupportedbyagrantfromSidraMedicine(SDR400048).S.G.T .andC.S.M.are supportedbygrantsawardedbytheNationalHealthandMedicalResearchCouncilofAustralia. F .S. andtheInstituteforResearchinBiomedicinearesupportedbytheHelmutHorten Foundation.Authorcontributions:Q.P ., M.O.,J.Bohlen,J.Puchan,A.A.A.,T .N., M.M.-F ., J.R., M.P ., R.Y ., T .Khan,A.-L.N.,M.M.A.A.,F .A.A., M.Migaud,A.M.,R.C.,S.B.,B.B.,C.S.M., M.Momenilandi,J.E.H.,J.Peel,F .M., M.W ., S.J.,P .B., R.L.,T .L.V ., M.R.L.M.R.,C.A.A.-F ., S.P ., M.Materna,C.S.,T .Kochetkov,N.M.,S.O.,S.G.T ., D.B.,V .B., F .S., S.B.-D.,J.Bustamante,andA.P . performedorsupervisedexperiments,generatedandanalyzeddata,andcontributedtothe manuscriptbyprovidingfiguresandtables.C.C.,D.R.,Y .S., A.C.,P .Z., andL.A.performedor supervisedcomputationalanalysesofdata.J.Bustamante,A.P ., M.Momenilandi,S.A.M.,M.K., C.F ., D.M.,M.S.,N.P ., andZ.C.evaluatedandrecruitedpatients.Q.P ., M.O.,S.B.-D.,J.Bustamante, J.-L.C.,andA.Pwrotethemanuscript.S.B.-D.,J.Bustamante,J.-L.C.,andA.P .supervisedthe project.Alloftheauthorseditedandapprovedthemanuscript.Competinginterests:The authorsdeclarethattheyhav enocompetinginterests.Dataandmaterialsavailability:The rawRNA-seqdatageneratedfromthisstudyhav e been deposited in theNCBI database under NCBISequenceReadArchive(SRA)projectaccessionno.PRJNA924565.Somedatafromcontrol individualswerepartoftheprojectsPRJNA818002,PRJNA898284,andPRJNA856671.The scRNA-seqdataassociatedwiththismanuscriptarealsoavailableintheMendeleydata repository under the DOI 10.17632/crn9b53g7v.1. The rest of the data needed to evaluate the conclusions in the paperarepresent in the paperor the Supplementary Materials. All rawand processeddataandbiologicalmaterials,includingimmortalizedcelllinesfrompatients,are available upon request from the corresponding authors under a material/datatransfer agreement. Funding Information: The HGMI laboratory was funded, in part, by the National Institute of Allergy and Infectious Diseases (NIAID), NIH [grant nos. R01AI095983 (to J.-L.C. and J. Bustamante), R01AI127564 (to J.-L.C. and A.P.), and U19AI162568 (to J.-L.C.)]; the National Center for Research Resources and the National Center for Advancing Sciences, NIH; the Rockefeller University; St. Giles Foundation; Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM); Paris Cit{\'e} University; the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID); the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01), Cross Lab Imagine Grant (The inborn errors of the keratinocyte-leukocyte cross-talk in humans to A.P.), ANR-GENMSMD (ANR-16-CE17-0005-01 to J. Bustamante), ANR FNS LTh-MSMD-CMCD (grant no. ANR-18-CE93-0008-01 to F.S. and A.P.), and ANRS project ECTZ170784-ANRS0073 and ANRS project ECTZ170784-ANRS0073 to S.B.-D.; the French Foundation for Medical Research (FRM; EQU201903007798); the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics); the Square Foundation, Grandir-Fonds de solidarit{\'e} pour l{\textquoteright}enfance; the SCOR Corporate Foundation for Science; and the Swiss National Science Foundation (no. 310030L_182728 to F.S.). Q.P. was supported by the Assistance Publique H{\^o}pitaux de Paris (Ann{\'e}e Recherche) and is supported by the MD-PhD program of INSERM (Ecole de l{\textquoteright}INSERM Liliane Bettencourt). J. Bohlen is supported by the EMBO fellowship program. J.R. was supported by the INSERM PhD program for doctors of pharmacy (Poste d{\textquoteright}accueil INSERM). J.R. and T.L.V. are supported by the Bettencourt-Schueller Foundation and the MD-PhD program of the Imagine Institute. A.-L.N. is supported by the Bettencourt Schueller Foundation and the International PhD program of the Imagine Institute. M.O. is supported by the David Rockefeller Graduate Program, the New York Hideyo Noguchi Memorial Society (HNMS), the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the National Cancer Institute (NCI) F99 Award (F99CA274708). A.A.A. and C.A.A.-F. are supported by Ministerio de Ciencia Tecnolog{\'i}a e Innovaci{\'o}n MINCIENCIAS, Colombia (111574455633/CT 713-2016 and 111584467551/CT 415-2020); the Movilidad Acad{\'e}mica ECOS-Nord/MINCIENCIAS, Colombia (CT 806-2018/046-2019); and the Comit{\'e} para el Desarrollo de la Investigaci{\'o}n, CODI-UdeA, Colombia (CT 2017-16003). R.Y. was supported by the Immune Deficiency Foundation and the Stony Wold-Herbert Fund. N.M. was supported by a grant from Sidra Medicine (SDR400048). S.G.T. and C.S.M. are supported by grants awarded by the National Health and Medical Research Council of Australia. F.S. and the Institute for Research in Biomedicine are supported by the Helmut Horten Foundation. Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",

year = "2023",

month = feb,

doi = "10.1126/sciimmunol.abq5204",

language = "English",

volume = "8",

journal = "Science immunology",

issn = "2470-9468",

publisher = "American Association for the Advancement of Science",

number = "80",

}

Philippot, Q, Ogishi, M, Bohlen, J, Puchan, J, Arias, AA, Nguyen, T, Martin-Fernandez, M, Conil, C, Rinchai, D, Momenilandi, M, Mahdaviani, SA, Keramatipour, M, Rosain, J, Yang, R, Khan, T, Neehus, AL, Materna, M, Han, JE, Peel, J, Mele, F, Weisshaar, M, Jovic, S, Bastard, P, Lévy, R, Le Voyer, T, Zhang, P, Renkilaraj, MRLM, Arango-Franco, CA, Pelham, S, Seeleuthner, Y, Pochon, M, Ata, MMA, Al Ali, F, Migaud, M, Soudée, C, Kochetkov, T, Molitor, A, Carapito, R, Bahram, S, Boisson, B, Fieschi, C, Mansouri, D, Marr, N, Okada, S, Shahrooei, M, Parvaneh, N, Chavoshzadeh, Z, Cobat, A, Bogunovic, D, Abel, L, Tangye, SG, Ma, CS, Béziat, V, Sallusto, F, Boisson-Dupuis, S, Bustamante, J, Casanova, JL & Puel, A 2023, 'Human IL-23 is essential for IFN-γ–dependent immunity to mycobacteria', Science immunology, vol. 8, no. 80, eabq5204. https://doi.org/10.1126/sciimmunol.abq5204

TY - JOUR

T1 - Human IL-23 is essential for IFN-γ–dependent immunity to mycobacteria

AU - Philippot, Quentin

AU - Ogishi, Masato

AU - Bohlen, Jonathan

AU - Puchan, Julia

AU - Arias, Andrés Augusto

AU - Nguyen, Tina

AU - Martin-Fernandez, Marta

AU - Conil, Clement

AU - Rinchai, Darawan

AU - Momenilandi, Mana

AU - Mahdaviani, Seyed Alireza

AU - Keramatipour, Mohammad

AU - Rosain, Jérémie

AU - Yang, Rui

AU - Khan, Taushif

AU - Neehus, Anna Lena

AU - Materna, Marie

AU - Han, Ji Eun

AU - Peel, Jessica

AU - Mele, Federico

AU - Weisshaar, Marc

AU - Jovic, Sandra

AU - Bastard, Paul

AU - Lévy, Romain

AU - Le Voyer, Tom

AU - Zhang, Peng

AU - Renkilaraj, Majistor Raj Luxman Maglorius

AU - Arango-Franco, Carlos A.

AU - Pelham, Simon

AU - Seeleuthner, Yoann

AU - Pochon, Mathieu

AU - Ata, Manar Mahmoud Ahmad

AU - Al Ali, Fatima

AU - Migaud, Mélanie

AU - Soudée, Camille

AU - Kochetkov, Tatiana

AU - Molitor, Anne

AU - Carapito, Raphael

AU - Bahram, Seiamak

AU - Boisson, Bertrand

AU - Fieschi, Claire

AU - Mansouri, Davood

AU - Marr, Nico

AU - Okada, Satoshi

AU - Shahrooei, Mohammad

AU - Parvaneh, Nima

AU - Chavoshzadeh, Zahra

AU - Cobat, Aurélie

AU - Bogunovic, Dusan

AU - Abel, Laurent

AU - Tangye, Stuart G.

AU - Ma, Cindy S.

AU - Béziat, Vivien

AU - Sallusto, Federica

AU - Boisson-Dupuis, Stéphanie

AU - Bustamante, Jacinta

AU - Casanova, Jean Laurent

AU - Puel, Anne

N1 - Funding Information: Acknowledgments:W ethankthepatientsandtheirfamiliesforplacingtheirtrustinus.W e thankthemembersofbothbranchesoftheLaboratoryofHumanGeneticsofInfectious Diseases.W ethankJ.MarkleandR.Martinez-Barricarteforhelpfuldiscussions.W ethank Y .Nemiro vskay a, M.W oollett, D.Liu,S.Boucherit,E.Williams,C.Rivalain,M.Chrabieh,and L. Lorenzo for administrative assistance. W e thank S. Elledge (Brigham and W omen ’s Hospital andHarvardMedicalSchool)forpro viding theVirScanphagelibraryusedinthisstudy.W e thanktheNIHT etr amerCoreFa cility (NTCF)forprovidingthe5-OP-RU–loadedMR1tetramer, whichwasdevelopedjointlywithJ.McCluskey ,J.Rossjohn,andD.Fairlie.Thefollowingreagent wasobtainedthroughBEIResources,NIAID,NIH:M.tuberculosis,strainH37Rv,whole-celllysate, NR-14822.Funding:TheHGMIlaboratorywasfunded,inpart,bytheNationalInstituteof AllergyandInfectiousDiseases(NIAID),NIH[grantnos.R01AI095983(toJ.-L.C.and J.Bustamante),R01AI127564(toJ.-L.C.andA.P .), andU19AI162568(toJ.-L.C.)];theNational CenterforResearchResourcesandtheNationalCenterforAdvancingSciences,NIH;the RockefellerUniversity;St.GilesFoundation;InstitutNationaldelaSantéetdelaRecherche Médicale(INSERM);ParisCitéUniversity;theIntegrativeBiologyofEmergingInfectious DiseasesLaboratoryofExcellence(ANR-10-LABX-62-IBEID);theFrenchNationalResearch Agency(ANR)underthe“InvestmentsfortheFuture”program(ANR-10-IAHU-01),CrossLab Imagine Grant (The inborn errors of the keratinocyte-leukocyte cross-talk in humans to A.P .), ANR-GENMSMD(ANR-16-CE17-0005-01toJ.Bustamante),ANRFNSL Th-MSMD-CMCD (grant no.ANR-18-CE93-0008-01toF .S. andA.P .), andANRSprojectECTZ170784-ANRS0073andANRS projectECTZ170784-ANRS0073toS.B.-D.;theFrenchFoundationforMedicalResearch(FRM; EQU201903007798); the European Union’s Horizon 2020 research and innovation program undergrantagreementno.824110(EASI-genomics);theSquareFoundation,Grandir-Fondsde solidarité pour l’enfance; the SCOR Corporate Foundation for Science; and the Swiss National ScienceFoundation(no.310030L_182728toF .S.). Q.P .wassupportedbytheAssistance PubliqueHôpitauxdeParis(AnnéeRecherche)andissupportedbytheMD-PhDprogramof INSERM (Ecole de l’INSERM Liliane Bettencourt). J. Bohlen is supported by the EMBO fellowship program.J.R.wassupportedbytheINSERMPhDprogramfordoctorsofpharmacy(Poste d’accueil INSERM). J.R. and T .L.V . are supported by the Bettencourt-Schueller Foundation and theMD-PhDprogramoftheImagineInstitute.A.-L.N.issupportedbytheBettencourtSchueller FoundationandtheInternationalPhDprogr am oftheImagineInstitute.M.O.issupportedby theDavidRockefellerGraduateProgram,theNewYorkHideyoNoguchiMemorialSociety (HNMS),theFunaiFoundationforInformationT echnology (FFIT),theHonjoInternational ScholarshipFoundation(HISF),andtheNationalCancerInstitute(NCI)F99A ward (F99CA274708).A.A.A.andC.A.A.-F .aresupportedbyMinisteriodeCienciaT ecnología e InnovaciónMINCIENCIAS,Colombia(111574455633/CT713-2016and111584467551/CT415-2020);theMovilidadAcadémicaECOS-Nord/MINCIENCIAS,Colombia(CT806-2018/046-2019); andtheComitéparaelDesarrollodelaInvestigación,CODI-UdeA,Colombia(CT2017-16003). R.Y .wassupportedbytheImmuneDeficiencyFoundationandtheStonyW old-Herbert Fund. N.M.wassupportedbyagrantfromSidraMedicine(SDR400048).S.G.T .andC.S.M.are supportedbygrantsawardedbytheNationalHealthandMedicalResearchCouncilofAustralia. F .S. andtheInstituteforResearchinBiomedicinearesupportedbytheHelmutHorten Foundation.Authorcontributions:Q.P ., M.O.,J.Bohlen,J.Puchan,A.A.A.,T .N., M.M.-F ., J.R., M.P ., R.Y ., T .Khan,A.-L.N.,M.M.A.A.,F .A.A., M.Migaud,A.M.,R.C.,S.B.,B.B.,C.S.M., M.Momenilandi,J.E.H.,J.Peel,F .M., M.W ., S.J.,P .B., R.L.,T .L.V ., M.R.L.M.R.,C.A.A.-F ., S.P ., M.Materna,C.S.,T .Kochetkov,N.M.,S.O.,S.G.T ., D.B.,V .B., F .S., S.B.-D.,J.Bustamante,andA.P . performedorsupervisedexperiments,generatedandanalyzeddata,andcontributedtothe manuscriptbyprovidingfiguresandtables.C.C.,D.R.,Y .S., A.C.,P .Z., andL.A.performedor supervisedcomputationalanalysesofdata.J.Bustamante,A.P ., M.Momenilandi,S.A.M.,M.K., C.F ., D.M.,M.S.,N.P ., andZ.C.evaluatedandrecruitedpatients.Q.P ., M.O.,S.B.-D.,J.Bustamante, J.-L.C.,andA.Pwrotethemanuscript.S.B.-D.,J.Bustamante,J.-L.C.,andA.P .supervisedthe project.Alloftheauthorseditedandapprovedthemanuscript.Competinginterests:The authorsdeclarethattheyhav enocompetinginterests.Dataandmaterialsavailability:The rawRNA-seqdatageneratedfromthisstudyhav e been deposited in theNCBI database under NCBISequenceReadArchive(SRA)projectaccessionno.PRJNA924565.Somedatafromcontrol individualswerepartoftheprojectsPRJNA818002,PRJNA898284,andPRJNA856671.The scRNA-seqdataassociatedwiththismanuscriptarealsoavailableintheMendeleydata repository under the DOI 10.17632/crn9b53g7v.1. The rest of the data needed to evaluate the conclusions in the paperarepresent in the paperor the Supplementary Materials. All rawand processeddataandbiologicalmaterials,includingimmortalizedcelllinesfrompatients,are available upon request from the corresponding authors under a material/datatransfer agreement. Funding Information: The HGMI laboratory was funded, in part, by the National Institute of Allergy and Infectious Diseases (NIAID), NIH [grant nos. R01AI095983 (to J.-L.C. and J. Bustamante), R01AI127564 (to J.-L.C. and A.P.), and U19AI162568 (to J.-L.C.)]; the National Center for Research Resources and the National Center for Advancing Sciences, NIH; the Rockefeller University; St. Giles Foundation; Institut National de la Santé et de la Recherche Médicale (INSERM); Paris Cité University; the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID); the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01), Cross Lab Imagine Grant (The inborn errors of the keratinocyte-leukocyte cross-talk in humans to A.P.), ANR-GENMSMD (ANR-16-CE17-0005-01 to J. Bustamante), ANR FNS LTh-MSMD-CMCD (grant no. ANR-18-CE93-0008-01 to F.S. and A.P.), and ANRS project ECTZ170784-ANRS0073 and ANRS project ECTZ170784-ANRS0073 to S.B.-D.; the French Foundation for Medical Research (FRM; EQU201903007798); the European Union’s Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics); the Square Foundation, Grandir-Fonds de solidarité pour l’enfance; the SCOR Corporate Foundation for Science; and the Swiss National Science Foundation (no. 310030L_182728 to F.S.). Q.P. was supported by the Assistance Publique Hôpitaux de Paris (Année Recherche) and is supported by the MD-PhD program of INSERM (Ecole de l’INSERM Liliane Bettencourt). J. Bohlen is supported by the EMBO fellowship program. J.R. was supported by the INSERM PhD program for doctors of pharmacy (Poste d’accueil INSERM). J.R. and T.L.V. are supported by the Bettencourt-Schueller Foundation and the MD-PhD program of the Imagine Institute. A.-L.N. is supported by the Bettencourt Schueller Foundation and the International PhD program of the Imagine Institute. M.O. is supported by the David Rockefeller Graduate Program, the New York Hideyo Noguchi Memorial Society (HNMS), the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the National Cancer Institute (NCI) F99 Award (F99CA274708). A.A.A. and C.A.A.-F. are supported by Ministerio de Ciencia Tecnología e Innovación MINCIENCIAS, Colombia (111574455633/CT 713-2016 and 111584467551/CT 415-2020); the Movilidad Académica ECOS-Nord/MINCIENCIAS, Colombia (CT 806-2018/046-2019); and the Comité para el Desarrollo de la Investigación, CODI-UdeA, Colombia (CT 2017-16003). R.Y. was supported by the Immune Deficiency Foundation and the Stony Wold-Herbert Fund. N.M. was supported by a grant from Sidra Medicine (SDR400048). S.G.T. and C.S.M. are supported by grants awarded by the National Health and Medical Research Council of Australia. F.S. and the Institute for Research in Biomedicine are supported by the Helmut Horten Foundation. Publisher Copyright: Copyright © 2023 The Authors, some rights reserved.

PY - 2023/2

Y1 - 2023/2

N2 - Patients with autosomal recessive (AR) IL-12p40 or IL-12Rβ1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium-inducible IFN-γ immunity in both Vδ2+ γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F–dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ–dependent immunity to Mycobacterium in at least two lymphocyte subsets.

AB - Patients with autosomal recessive (AR) IL-12p40 or IL-12Rβ1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium-inducible IFN-γ immunity in both Vδ2+ γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F–dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ–dependent immunity to Mycobacterium in at least two lymphocyte subsets.

UR - http://www.scopus.com/inward/record.url?scp=85147111665&partnerID=8YFLogxK

U2 - 10.1126/sciimmunol.abq5204

DO - 10.1126/sciimmunol.abq5204

M3 - Article

C2 - 36763636

AN - SCOPUS:85147111665

SN - 2470-9468

VL - 8

JO - Science immunology

JF - Science immunology

IS - 80

M1 - eabq5204

ER -

Human IL-23 is essential for IFN-γ–dependent immunity to mycobacteria

Abstract

Access to Document

Fingerprint

Cite this