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 | |
State | Published - Feb 2023 |
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In: Science immunology, Vol. 8, No. 80, eabq5204, 02.2023.
Research output: Contribution to journal › Article › peer-review
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 -