Humans homozygous for rare or common hypomorphic IL23R variants are prone to tuberculosis

https://orcid.org/0000-0003-3278-5159 Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing *

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

Laura E. Kilpatrick

https://orcid.org/0000-0001-6331-5606 Formal analysis, Funding acquisition, Investigation, Visualization, Writing - original draft, Writing - review & editing *

3Division of Biomolecular Science and Medicinal Chemistry,

School of Pharmacy, University of Nottingham

, Nottingham,

4Centre of Membrane Proteins and Receptors,

University of Birmingham and University of Nottingham

, The Midlands, Nottingham,

Clément Conil

https://orcid.org/0000-0002-9412-1932 Data curation, Formal analysis, Software, Validation, Writing - original draft, Writing - review & editing *

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

Quentin Philippot

https://orcid.org/0000-0003-3429-9605 Conceptualization, Formal analysis, Investigation, Writing - original draft, Writing - review & editing *

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

Masato Ogishi

https://orcid.org/0000-0003-2421-7389 Investigation, Methodology, Software, Writing - review & editing **

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Joseph Vellutini

https://orcid.org/0009-0008-1655-0038 Data curation, Formal analysis, Resources, Software, Visualization **

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Ji Eun Han

https://orcid.org/0000-0003-1112-9320 Methodology, Resources, Validation

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Narelle Keating

https://orcid.org/0000-0002-4392-0806 Investigation, Visualization

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

Hailun Li

https://orcid.org/0000-0002-0764-2837 Investigation

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

Geetha Rao

https://orcid.org/0009-0007-2744-9309 Formal analysis, Investigation

Garvan Institute of Medical Research

, Darlinghurst,

Australia

7Faculty of Medicine and Health,

School of Clinical Medicine, University of New South Wales Sydney

, Kensington,

Australia

Jonathan Bohlen

https://orcid.org/0000-0003-0458-9484 Conceptualization, Investigation, Methodology, Supervision, Validation, Writing - review & editing

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

8Gene Center and Department of Biochemistry,

Ludwig-Maximilians-Universität

, Munich,

Germany

9Department of Pediatrics,

Dr. von Hauner Childrens Hospital, LMU Klinikum

, Munich,

Germany

German Center for Child and Adolescent Health (DZKJ)

, Munich,

Germany

Charles S. Lay

https://orcid.org/0000-0002-3060-6762 Investigation, Methodology

4Centre of Membrane Proteins and Receptors,

University of Birmingham and University of Nottingham

, The Midlands, Nottingham,

11Division of Physiology,

Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham

, Nottingham,

Simon Platt

https://orcid.org/0000-0002-8418-3646 Investigation, Methodology, Writing - original draft

4Centre of Membrane Proteins and Receptors,

University of Birmingham and University of Nottingham

, The Midlands, Nottingham,

11Division of Physiology,

Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham

, Nottingham,

Gaspard Kerner

https://orcid.org/0000-0003-0146-9428 Formal analysis

12Human Evolutionary Genetics Unit,

Institut Pasteur, Paris Cité University, CNRS UMR2000

, Paris,

France

Elsa Feredj

https://orcid.org/0000-0001-8301-0850 Investigation

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Jessica N. Peel

https://orcid.org/0000-0002-1894-8882 Writing - review & editing

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Mana Momenilandi

https://orcid.org/0000-0002-5340-2762 Investigation, Resources

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

Yoann Seeleuthner

https://orcid.org/0009-0000-2670-6026 Data curation, Resources

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

Candice Lainé

https://orcid.org/0000-0003-3258-6969 Investigation, Resources

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

Camille Soudée

https://orcid.org/0009-0002-1445-7223 Investigation

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

Claire Leloup

https://orcid.org/0000-0003-3525-0854 Investigation

13Immunoregulation Unit, Department of Immunology,

Institut Pasteur, Paris Cité University

, Paris,

France

Cecile Debuisson Resources

14General Pediatrics Department,

Hôpital des Enfants, Centre Hospitalier Universitaire de Toulouse

, Toulouse,

France

Fanny Lanternier

https://orcid.org/0000-0003-3800-4683 Investigation, Visualization

Service de Maladies Infectieuses et Tropicales, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)

, Paris,

France

16Translational Mycology Research Group, Mycology Department,

National Reference Center for Invasive Mycoses and Antifungals, Institut Pasteur, Paris Cité University

, Paris,

France

Samuel Bitoun

https://orcid.org/0000-0003-0891-2269 Data curation, Formal analysis, Investigation, Validation, Writing - review & editing

17Department of Rheumatology,

AP-HP, Hôpital Bicêtre, Université Paris-Saclay, INSERM, CEA, UMR 1184, FHU CARE

, Le Kremlin Bicêtre,

France

Stephan Pavy

https://orcid.org/0009-0008-9618-4241 Resources

17Department of Rheumatology,

AP-HP, Hôpital Bicêtre, Université Paris-Saclay, INSERM, CEA, UMR 1184, FHU CARE

, Le Kremlin Bicêtre,

France

Xavier Mariette

https://orcid.org/0000-0002-4244-5417 Resources, Writing - review & editing

17Department of Rheumatology,

AP-HP, Hôpital Bicêtre, Université Paris-Saclay, INSERM, CEA, UMR 1184, FHU CARE

, Le Kremlin Bicêtre,

France

Aniss Rafik

https://orcid.org/0000-0001-7474-6348 Conceptualization, Investigation, Resources

18Genetics Unit,

Mohamed V Military Hospital

, Hay Riad,

Morocco

19Department of Pulmonology,

Military Hospital Mohammed V, Medical and Pharmacy School of Rabat, Mohammed V University

, Rabat,

Morocco

Hanaa Skhoun

https://orcid.org/0000-0002-4081-1604 Conceptualization, Investigation, Resources

18Genetics Unit,

Mohamed V Military Hospital

, Hay Riad,

Morocco

Hanane El Ouazzani

https://orcid.org/0009-0009-9334-9722 Conceptualization, Investigation, Resources

19Department of Pulmonology,

Military Hospital Mohammed V, Medical and Pharmacy School of Rabat, Mohammed V University

, Rabat,

Morocco

Ismael Abderahmani-Ghorfi

https://orcid.org/0000-0001-6403-0098 Conceptualization, Investigation, Resources

19Department of Pulmonology,

Military Hospital Mohammed V, Medical and Pharmacy School of Rabat, Mohammed V University

, Rabat,

Morocco

Jamila El-Baghdadi

https://orcid.org/0000-0002-1920-2310 Conceptualization, Investigation, Resources

18Genetics Unit,

Mohamed V Military Hospital

, Hay Riad,

Morocco

Andrés Baena

https://orcid.org/0000-0003-1309-1020 Resources

20Facultad de Medicina,

Grupo de Inmunología Celular e Inmunogenética (GICIG), Universidad de Antioquia (UdeA)

, Medellín,

Colombia

21Departamento de Microbiología y Parasitología,

Facultad de Medicina, UdeA

, Medellín,

Colombia

Manuela Tejada-Giraldo

https://orcid.org/0000-0001-8868-3544 Investigation

20Facultad de Medicina,

Grupo de Inmunología Celular e Inmunogenética (GICIG), Universidad de Antioquia (UdeA)

, Medellín,

Colombia

22Inborn Errors of Immunity Group, Department of Microbiology and Parasitology,

School of Medicine, UdeA

, Medellín,

Colombia

Luis Fernando Barrera

https://orcid.org/0000-0002-6108-6747 Investigation, Resources

20Facultad de Medicina,

Grupo de Inmunología Celular e Inmunogenética (GICIG), Universidad de Antioquia (UdeA)

, Medellín,

Colombia

Instituto de Investigaciones Médicas, UdeA

, Medellín,

Colombia

Andrés Augusto Arias

https://orcid.org/0000-0002-9478-8403 Investigation, Resources

22Inborn Errors of Immunity Group, Department of Microbiology and Parasitology,

School of Medicine, UdeA

, Medellín,

Colombia

School of Microbiology, UdeA

, Medellín,

Colombia

Giovanna Fabio

https://orcid.org/0000-0002-8805-2942 Resources, Visualization

25Department of Internal Medicine,

Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ca' Granda Ospedale Maggiore Policlinico

, Milan,

Italy

Maria Carrabba

https://orcid.org/0000-0002-0717-9096 Investigation, Resources

25Department of Internal Medicine,

Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ca' Granda Ospedale Maggiore Policlinico

, Milan,

Italy

Melike Emiroglu

https://orcid.org/0000-0003-1307-0246 Data curation, Resources, Supervision

26Division of Pediatric Infectious Diseases, Department of Pediatrics,

Selcuk University Faculty of Medicine

, Konya,

Turkey

Liliana Bezrodnik

https://orcid.org/0000-0001-9812-2468 Resources

Grupo de Inmunología-Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas (IMIPP-CONICET), Hospital de Niños “Dr. Ricardo Gutierrez”

, Buenos Aires,

Argentina

Center for Clinical Immunology

, Buenos Aires,

Argentina

Loubna El Zein

https://orcid.org/0000-0003-2393-1150 Investigation, Resources

29Biology Department,

Lebanese University

, Beirut,

Lebanon

Hassan Hammoud Resources

Saint George Hospital

, Beirut,

Lebanon

Peter K. Gregersen

https://orcid.org/0000-0003-1613-1518 Data curation

Robert S. Boas Center for Genomics and Human Genetics, Institute of Molecular Medicine, Feinstein Institutes for Medical Research

, Manhasset, NY,

USA

Benjamin Terrier

https://orcid.org/0000-0001-6612-7336 Data curation, Writing - review & editing

32Department of Internal Medicine,

Cochin Hospital, University of Paris, AP-HP

, Paris,

France

Rafael Leon Lopez

https://orcid.org/0000-0002-8102-9520 Resources

Unidad de Gestión Clínica de Cuidados Intensivos, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba (UCO)

, Córdoba,

Spain

Marion Touzet

https://orcid.org/0009-0004-8107-6548 Investigation

34Department of Internal Medicine,

Hospital Centre Avignon

, Avignon,

France

Vincent Pestre

https://orcid.org/0000-0001-8825-5670 Investigation, Resources

35Department of Pediatric Hematology and Oncology,

Centre Hospitalo-Universitaire de Toulouse

, Toulouse,

France

Marlène Pasquet

https://orcid.org/0000-0001-6919-8383 Resources

35Department of Pediatric Hematology and Oncology,

Centre Hospitalo-Universitaire de Toulouse

, Toulouse,

France

Lars Rogge

https://orcid.org/0000-0003-1262-9204 Investigation, Resources, Writing - review & editing

13Immunoregulation Unit, Department of Immunology,

Institut Pasteur, Paris Cité University

, Paris,

France

Michael Fayon

https://orcid.org/0000-0002-1238-2128 Investigation, Validation

36CHU Bordeaux, Département de Pédiatrie,

CIC-P INSERM 1401

, Bordeaux,

France

Centre de Recherche Cardio-thoracique de Bordeaux, Université de Bordeaux, INSERM U1045

, Bordeaux,

France

François Galode

https://orcid.org/0000-0002-1489-4514 Resources

38Pediatric Pulmonology,

Pellegrin Hospital, Bordeaux University Hospital

, Bordeaux,

France

Centre Constitutif des Maladies Respiratoires Rares de L’enfant (RESPIRARE)

, Bordeaux,

France

Eric Jeziorski

https://orcid.org/0000-0003-0318-3044 Resources

Service Urgences Post-urgences Pédiatriques, PCCEI, CeRéMAIA, Univ Montpellier, CHU Montpellier

, Montpellier,

France

Darragh Duffy

https://orcid.org/0000-0002-8875-2308 Resources, Writing - review & editing

41Translational Immunology Unit,

Institut Pasteur, Paris Cité University

, Paris,

France

Single Cell Biomarkers UTechS, Institut Pasteur, Paris Cité University

, Paris,

France

Lluis Quintana-Murci

https://orcid.org/0000-0003-2429-6320 Resources, Validation

12Human Evolutionary Genetics Unit,

Institut Pasteur, Paris Cité University, CNRS UMR2000

, Paris,

France

Etienne Patin

https://orcid.org/0000-0002-9911-4459 Resources

12Human Evolutionary Genetics Unit,

Institut Pasteur, Paris Cité University, CNRS UMR2000

, Paris,

France

Charlotte Cunningham-Rundles

https://orcid.org/0000-0003-0725-0320 Resources

43Department of Medicine,

Icahn School of Medicine at Mount Sinai

, New York, NY,

USA

44Department of Pediatrics,

Icahn School of Medicine at Mount Sinai

, New York, NY,

USA

Isabelle Meyts

https://orcid.org/0000-0003-1214-0302 Data curation, Funding acquisition, Investigation, Resources, Writing - review & editing

45Department of Pediatrics,

University Hospitals Leuven

, Leuven,

Belgium

46Department of Microbiology,

Immunology and Transplantation, KU Leuven

, Leuven,

Belgium

Shen-Ying Zhang

https://orcid.org/0000-0002-9449-3672 Resources, Writing - review & editing

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Qian Zhang

https://orcid.org/0000-0002-9040-3289 Resources

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Emmanuelle Jouanguy

https://orcid.org/0000-0002-7358-9157 Resources, Writing - review & editing

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Bertrand Boisson

https://orcid.org/0000-0001-5240-3555 Resources

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Jérémie Rosain

https://orcid.org/0000-0002-2822-161X Resources

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP

, Paris,

France

Vivien Béziat

https://orcid.org/0000-0002-4020-824X Formal analysis

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Mohammad Shahrooei

https://orcid.org/0000-0002-4974-3441 Conceptualization, Data curation, Formal analysis, Investigation, Validation

Dr. Shahrooei Lab

, Tehran,

Iran

Seyed Alireza Mahdaviani

https://orcid.org/0000-0001-6224-4797 Conceptualization, Investigation, Project administration, Validation, Writing - review & editing

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences

, Tehran,

Iran

Nima Rezaei

https://orcid.org/0000-0002-3836-1827 Conceptualization, Data curation, Investigation, Methodology, Project administration, Supervision, Validation, Writing - review & editing

Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences

, Tehran,

Iran

Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN)

, Tehran,

Iran

Nima Parvaneh

https://orcid.org/0000-0002-3397-9716 Investigation, Resources

52Division of Allergy and Clinical Immunology, Department of Pediatrics,

Tehran University of Medical Sciences

, Tehran,

Iran

Zahra Chavoshzadeh

https://orcid.org/0000-0003-1869-8630 Resources

Pediatric Infections Research Center, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences

, Tehran,

Iran

Niloufar Yazdanpanah

https://orcid.org/0000-0003-4333-2163 Resources

Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN)

, Tehran,

Iran

Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences

, Tehran,

Iran

Nathalie Aladjidi

https://orcid.org/0000-0003-0231-4460 Resources

Pediatric Hemato-Immunology, Pellegrin Hospital, Bordeaux University Hospital, CIC1401, INSERM CICP

, Bordeaux,

France

Centre de Compétence des Déficits Immunitaires Héréditaires (CEREDIH)

, Bordeaux,

France

Antoni Noguera-Julian

https://orcid.org/0000-0001-7485-0583 Investigation, Writing - review & editing

56Pediatric Infectious Diseases Department,

Infectious Diseases and Systemic Inflammatory Response in Pediatrics, Institut de Recerca Sant Joan de Déu (IRSJD), Hospital Sant Joan de Déu

, Barcelona,

Spain

Centre for Biomedical Network Research on Epidemiology and Public Health (CIBERESP)

, Madrid,

Spain

58Departament de Cirurgia i Especialitats Medicoquirúrgiques,

Facultat de Medicina I Ciències de La Salut, Universitat de Barcelona

, Barcelona,

Spain

Ana Esteve-Solé

https://orcid.org/0000-0002-0542-0587 Investigation, Resources, Writing - review & editing

Study Group for Immune Dysfunction Diseases in Children (GEMDIP), Institut de Recerca Sant Joan de Déu (IRSJD)

, Barcelona,

Spain

60Clinical Immunology and Primary Immunodeficiencies Unit,

Pediatric Allergy and Clinical Immunology

, Department Hospital Sant Joan de Déu, Barcelona,

Spain

Laia Alsina

https://orcid.org/0000-0002-3559-0018 Data curation, Investigation, Validation, Writing - review & editing

58Departament de Cirurgia i Especialitats Medicoquirúrgiques,

Facultat de Medicina I Ciències de La Salut, Universitat de Barcelona

, Barcelona,

Spain

Study Group for Immune Dysfunction Diseases in Children (GEMDIP), Institut de Recerca Sant Joan de Déu (IRSJD)

, Barcelona,

Spain

60Clinical Immunology and Primary Immunodeficiencies Unit,

Pediatric Allergy and Clinical Immunology

, Department Hospital Sant Joan de Déu, Barcelona,

Spain

Davood Mansouri

https://orcid.org/0000-0002-0564-8282 Resources

Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences

, Tehran,

Iran

61Department of Clinical Immunology and Infectious Diseases,

NRITLD, Shahid Beheshti University of Medical Sciences

, Tehran,

Iran

The Clinical Tuberculosis and Epidemiology Research Center, NRITLD, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences

, Tehran,

Iran

Sevgi Keles

https://orcid.org/0000-0001-7344-8947 Data curation, Investigation

63Division of Pediatric Allergy and Immunology, Meram Faculty of Medicine,

Necmettin Erbakan University

, Konya,

Turkey

Mediha Gonenc Ortakoylu

https://orcid.org/0000-0001-6106-0080 Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing

64Department of Pulmonary Medicine,

Yedikule Chest Diseases and Thoracic Surgery Training and Research Hospital, University of Health Sciences Turkey

, Istanbul,

Turkey

Deniz Aygun

https://orcid.org/0000-0002-7830-7155 Data curation

65Department of Paediatric Infectious Diseases,

Cerrahpasa Faculty of Medicine, Istanbul Cerrahpasa-University

, Istanbul,

Turkey

Esra Yucel

https://orcid.org/0000-0003-3712-2522 Resources

66Department of Pediatric Allergy and Immunology,

Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa

, Istanbul,

Turkey

Ayca Kiykim

https://orcid.org/0000-0001-5821-3963 Resources, Writing - review & editing

66Department of Pediatric Allergy and Immunology,

Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa

, Istanbul,

Turkey

Yildiz Camcioglu

https://orcid.org/0000-0002-4796-6828 Data curation

67Division of Infectious Diseases and Clinical Immunology,

Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa

, Istanbul,

Turkey

Cindy S. Ma

https://orcid.org/0000-0001-5387-8413 Funding acquisition, Methodology, Supervision, Writing - review & editing

Garvan Institute of Medical Research

, Darlinghurst,

Australia

7Faculty of Medicine and Health,

School of Clinical Medicine, University of New South Wales Sydney

, Kensington,

Australia

Stuart G. Tangye

https://orcid.org/0000-0002-5360-5180 Funding acquisition, Project administration, Supervision, Validation, Writing - review & editing

Garvan Institute of Medical Research

, Darlinghurst,

Australia

7Faculty of Medicine and Health,

School of Clinical Medicine, University of New South Wales Sydney

, Kensington,

Australia

Peng Zhang

https://orcid.org/0000-0002-6129-567X Data curation, Formal analysis, Software

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Laurent Abel

https://orcid.org/0000-0001-7016-6493 Formal analysis, Writing - review & editing

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Peter D. Craggs

https://orcid.org/0000-0002-9546-6617 Funding acquisition, Project administration ***

Chemical Biology, Medicine Design, GlaxoSmithKline

, Stevenage,

69Crick-GSK Biomedical Linklabs,

Medicine Design, GlaxoSmithKline

, Stevenage,

Jean-Laurent Casanova

https://orcid.org/0000-0002-7782-4169 Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing - original draft, Writing - review & editing ***

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

70Department of Pediatrics,

Necker Hospital for Sick Children, AP-HP

, Paris,

France

Howard Hughes Medical Institute

, New York, NY,

USA

Aurélie Cobat

https://orcid.org/0000-0001-7209-6257 Methodology, Supervision, Validation, Writing - review & editing ***

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Anne Puel

https://orcid.org/0000-0003-2603-0323 Conceptualization, Funding acquisition, Resources, Supervision, Writing - original draft, Writing - review & editing ***

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Jacinta Bustamante

https://orcid.org/0000-0002-3439-2482 Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Supervision, Writing - original draft, Writing - review & editing ***

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP

, Paris,

France

Stephen J. Hill

https://orcid.org/0000-0002-4424-239X Funding acquisition, Investigation, Visualization, Writing - original draft, Writing - review & editing ***

4Centre of Membrane Proteins and Receptors,

University of Birmingham and University of Nottingham

, The Midlands, Nottingham,

11Division of Physiology,

Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham

, Nottingham,

Stéphanie Boisson-Dupuis

https://orcid.org/0000-0002-7115-116X Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing ***

1Laboratory of Human Genetics of Infectious Diseases,

Necker Branch, INSERM U1163, Necker Hospital for Sick Children

, Paris,

France

Imagine Institute, Paris Cité University

, Paris,

France

5St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch,

Rockefeller University

, New York, NY,

USA

Correspondence to Stéphanie Boisson-Dupuis: [email protected]

Jean-Laurent Casanova: [email protected]

D. Olguín Calderón, L.E. Kilpatrick, C. Conil, and Q. Philippot contributed equally to this paper.

M. Ogishi and J. Vellutini contributed equally to this paper.

***

P.D. Craggs, J.-L. Casanova, A. Cobat, A. Puel, J. Bustamante, S.J. Hill, and S. Boisson-Dupuis contributed equally to this paper.

Disclosures: L. Kilpatrick reported grants from Medical Research Council during the conduct of the study. Q. Philippot reported research grants from the Bettencourt Schueller Foundation under the CCA Inserm Bettencourt program, Air Liquide Foundation, Fondation du Souffle, and Agence Nationale de la Recherche. L. Rogge reported grants from Johnson & Johnson outside the submitted work. I. Meyts reported other from CSL Behring, Boehringer Ingelheim, and Takeda outside the submitted work. S.J. Hill reported grants from Medical Research Council UK, Biotechnology and Biological Sciences Research Council UK, and GSK during the conduct of the study. No other disclosures were reported.

Received: October 27 2025

Revision Received: February 20 2026

Accepted: April 23 2026

Online ISSN: 1540-9538

Print ISSN: 0022-1007

Funding

Funder(s):

National Institute of Allergy and Infectious Diseases

Award Id(s):
R01AI095983
,
R01AI127564

Funder(s):

National Institutes of Health

Funder(s):

Rockefeller University

Funder(s):

St. Giles Foundation

Funder(s):

Howard Hughes Medical Institute

Funder(s):

Institut National de la Santé et de la Recherche Médicale

Funder(s):

Paris Cité University

Funder(s):

Agence Nationale de la Recherche

Award Id(s):
ANR-10-IAHU-01
,
ANR-10-LABX-62-IBEID
,
ANR-22-CE92-0008

Funder(s):

Agence Nationale de Recherches sur le Sida et les Hépatites Virales

Award Id(s):
ECTZ170784-ANRS0073
,
ANRS0787-ECTZ323676
,
ECTZ293125
,
ECTZ293911

Funder(s):

French Foundation for Medical Research

Award Id(s):
EQU202503020018
,
FDM202406018939

Funder(s):

European Union’s Horizon 2020 Research and Innovation Program

Award Id(s):
824110

Funder(s):

Square Foundation

Funder(s):

Grandir - Fonds de Solidarité pourL’enfance

Funder(s):

General Atlantic Foundation

Funder(s):

Assistance Publique Hôpitaux de Paris

Funder(s):

European Molecular Biology Organization

Funder(s):

Marie Curie Research

Funder(s):

Collège des Universitaires des Maladies Infectieuses et Tropicales

Funder(s):

European Society of Clinical Microbiology and Infectious Diseases

Funder(s):

Réunion Interdisciplinaire de Chimiothérapie Anti-Infectieuse

Funder(s):

Imagine Institute

Funder(s):

Funai Foundation for Information Technology

Funder(s):

Honjo International Scholarship Foundation

Funder(s):

New York Hideyo Noguchi Memorial Society

Funder(s):

Medical Research Council

Award Id(s):
MR/W016176/1

Funder(s):

Biotechnology and Biological Sciences Research Council

Award Id(s):
BB/S507027/1

Funder(s):

Subdirección General de Evaluación y Formento de la Investigación Sanitaria

Funder(s):

Fondo Europeo de Desarrollo Regional

Award Id(s):
PI15/01094

Funder(s):

Ministerio de Ciencia, Tecnología e Innovación

Award Id(s):
111584467551/CT 415-2020

Funder(s):

Jeffrey Modell Foundation

Funder(s):

Fundación Diana García de Olarte para las Inmunodeficiencias Primarias

Funder(s):

National Health and Medical Research Council

Award Id(s):
2017463
,
1176665

Funder(s):

National Center for Research Resources

Funder(s):

National Center for Advancing Sciences

Award Id(s):
UL1TR001866

Funder(s):

Labex-IBEID

Funder(s):

Fonds Wetenschappelijk Onderzoek

Award Id(s):
G1805826N

2026

Olguín Calderón et al.

This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.

J Exp Med (2026) 223 (8): e20252236.

https://doi.org/10.1084/jem.20252236

Homozygosity for rare loss-of-function IL23R variants abolishes IL-23–dependent IFN-γ production by lymphocytes, including NK and innate-like T cells, thereby underlying clinical disease due to weakly virulent mycobacterial species. We report selective enrichment in homozygosity for four hypomorphic IL23R variants in our cohort of patients with tuberculosis. Three of these IL23R alleles are rare (G300V, G149R, and L372F), with a minor allele frequency (MAF) under 1%, but the fourth (R381Q) is surprisingly common, with an MAF as high as 10.2% in certain populations. The other 15 missense alleles found in the homozygous state in public databases are isomorphic. The four hypomorphic IL-23R variants identified dimerize with IL-12Rβ1 and bind IL-23. However, their function is impaired by low levels of cell surface expression (R381Q, G300V) and/or as a consequence of conformational changes altering agonist efficacy. IFN-γ production in response to IL-23 is impaired in innate-like T cells and NK cells. These data suggest that recessive partial IL-23R deficiency, whether due to rare or common variants, confers a predisposition to tuberculosis while preserving immunity to less virulent mycobacteria.

2026

Olguín Calderón et al.

This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.

You do not currently have access to this content.

Don't already have an account? Register

Humans homozygous for rare or common hypomorphic IL23R variants are prone to tuberculosis

Sign in

Client Account

Sign in via your Institution

Suggested Content

Email alerts

Sharing Unavailable