Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria

Rui Yang; Federico Mele; Lisa Worley; David Langlais; Jérémie Rosain; Ibithal Benhsaien; Houda Elarabi; Carys A Croft; Jean-Marc Doisne; Peng Zhang; Marc Weisshaar; David Jarrossay; Daniela Latorre; Yichao Shen; Jing Han; Masato Ogishi; Conor Gruber; Janet Markle; Fatima Al Ali; Mahbuba Rahman; Taushif Khan; Yoann Seeleuthner; Gaspard Kerner; Lucas T Husquin; Julia L Maclsaac; Mohamed Jeljeli; Abderrahmane Errami; Fatima Ailal; Michael S Kobor; Carmen Oleaga-Quintas; Manon Roynard; Mathieu Bourgey; Jamila El Baghdadi; Stéphanie Boisson-Dupuis; Anne Puel; Fréderic Batteux; Flore Rozenberg; Nico Marr; Qiang Pan-Hammarström; Dusan Bogunovic; Lluis Quintana-Murci; Thomas Carroll; Cindy S Ma; Laurent Abel; Aziz Bousfiha; James P Di Santo; Laurie H Glimcher; Philippe Gros; Stuart G Tangye; Federica Sallusto; Jacinta Bustamante; Jean-Laurent Casanova

doi:10.1016/j.cell.2020.10.046

Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria

Cell. 2020 Dec 23;183(7):1826-1847.e31. doi: 10.1016/j.cell.2020.10.046. Epub 2020 Dec 8.

Authors

Rui Yang¹, Federico Mele², Lisa Worley³, David Langlais⁴, Jérémie Rosain⁵, Ibithal Benhsaien⁶, Houda Elarabi⁷, Carys A Croft⁸, Jean-Marc Doisne⁹, Peng Zhang¹⁰, Marc Weisshaar¹¹, David Jarrossay², Daniela Latorre¹¹, Yichao Shen¹⁰, Jing Han¹⁰, Masato Ogishi¹⁰, Conor Gruber¹², Janet Markle¹⁰, Fatima Al Ali¹³, Mahbuba Rahman¹³, Taushif Khan¹³, Yoann Seeleuthner⁵, Gaspard Kerner⁵, Lucas T Husquin¹⁴, Julia L Maclsaac¹⁵, Mohamed Jeljeli¹⁶, Abderrahmane Errami¹⁷, Fatima Ailal⁶, Michael S Kobor¹⁵, Carmen Oleaga-Quintas⁵, Manon Roynard⁵, Mathieu Bourgey¹⁸, Jamila El Baghdadi¹⁹, Stéphanie Boisson-Dupuis²⁰, Anne Puel²⁰, Fréderic Batteux¹⁶, Flore Rozenberg²¹, Nico Marr²², Qiang Pan-Hammarström²³, Dusan Bogunovic¹², Lluis Quintana-Murci²⁴, Thomas Carroll²⁵, Cindy S Ma³, Laurent Abel²⁰, Aziz Bousfiha⁶, James P Di Santo⁹, Laurie H Glimcher²⁶, Philippe Gros²⁷, Stuart G Tangye³, Federica Sallusto²⁸, Jacinta Bustamante²⁹, Jean-Laurent Casanova³⁰

Affiliations

¹ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA. Electronic address: [email protected].
² Center of Medical Immunology, Institute for Research in Biomedicine, Faculty of Biomedical Sciences, University of Italian Switzerland (USI), 6500 Bellinzona, Switzerland.
³ Garvan Institute of Medical Research, Darlinghurst 2010, NSW, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst 2010, NSW, Australia.
⁴ Department of Human Genetics, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 0G1, Canada; McGill University Genome Center, McGill Research Centre on Complex Traits, Montreal, QC H3A 0G1, Canada.
⁵ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University of Paris, Imagine Institute, 75015 Paris, France.
⁶ Laboratory of Clinical Immunology, Inflammation and Allergy, Faculty of Medicine and Pharmacy of Casablanca, King Hassan II University, 20460 Casablanca, Morocco; Clinical Immunology Unit, Department of Pediatric Infectious Diseases, Children's Hospital, CHU Averroes, 20460 Casablanca, Morocco.
⁷ Pediatrics Department, Hassan II Hospital, 80030 Dakhla, Morocco.
⁸ Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; INSERM U1223, 75015 Paris, France; University of Paris, 75006 Paris, France.
⁹ Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; INSERM U1223, 75015 Paris, France.
¹⁰ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA.
¹¹ Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.
¹² Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹³ Research Branch, Sidra Medicine, Doha, PO 26999, Qatar.
¹⁴ Human Evolutionary Genetics Unit, CNRS UMR2000, Institut Pasteur, 75015 Paris, France.
¹⁵ BC Children's Hospital Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
¹⁶ University of Paris, 75006 Paris, France; Immunology Laboratory, Cochin Hospital, AH-HP, 75014 Paris, France.
¹⁷ Laboratory of Clinical Immunology, Inflammation and Allergy, Faculty of Medicine and Pharmacy of Casablanca, King Hassan II University, 20460 Casablanca, Morocco.
¹⁸ McGill University Genome Center, McGill Research Centre on Complex Traits, Montreal, QC H3A 0G1, Canada; Canadian Centre for Computational Genomics, Montreal, QC H3A 0G1, Canada.
¹⁹ Genetics Unit, Military Hospital Mohamed V, 10100 Rabat, Morocco.
²⁰ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University of Paris, Imagine Institute, 75015 Paris, France.
²¹ University of Paris, 75006 Paris, France; Virology Laboratory, Cochin Hospital, AH-HP, 75014 Paris, France.
²² Research Branch, Sidra Medicine, Doha, PO 26999, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, PO 34110, Qatar.
²³ Department of Biosciences and Nutrition, Karolinska Institutet, 17177 Stockholm, Sweden.
²⁴ Human Evolutionary Genetics Unit, CNRS UMR2000, Institut Pasteur, 75015 Paris, France; Chair of Human Genomics and Evolution, Collège de France, 75005 Paris, France.
²⁵ Bioinformatics Resource Center, The Rockefeller University, New York, NY 10065, USA.
²⁶ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
²⁷ McGill University Genome Center, McGill Research Centre on Complex Traits, Montreal, QC H3A 0G1, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
²⁸ Center of Medical Immunology, Institute for Research in Biomedicine, Faculty of Biomedical Sciences, University of Italian Switzerland (USI), 6500 Bellinzona, Switzerland; Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.
²⁹ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University of Paris, Imagine Institute, 75015 Paris, France; Study Center for Primary Immunodeficiencies, Necker Children Hospital, AP-HP, 75015 Paris, France.
³⁰ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University of Paris, Imagine Institute, 75015 Paris, France; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France; Howard Hughes Medical Institute, New York, NY, USA. Electronic address: [email protected].

Abstract

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2⁺ γδ T lymphocytes, and of Mycobacterium-non reactive classic T_H1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8⁺ αβ T and non-classic CD4⁺ αβ T_H1^∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2⁺ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8⁺ αβ T, and CD4⁺ αβ T_H1^∗ cells unable to compensate for this deficit.

Keywords: IFN-γ; Mendelian susceptibility to mycobacterial disease; T-bet; immunodeficiency; inborn errors of immunity; innate lymphocyte; innate-like adaptive lymphocyte; mycobacterium.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity*
Amino Acid Sequence
Base Sequence
Cell Lineage
Child, Preschool
Chromatin / metabolism
CpG Islands / genetics
DNA Methylation / genetics
Dendritic Cells / metabolism
Epigenesis, Genetic
Female
Homozygote
Humans
INDEL Mutation / genetics
Immunity, Innate*
Infant
Interferon-gamma / immunology*
Interferon-gamma / metabolism
Killer Cells, Natural / cytology
Killer Cells, Natural / metabolism
Loss of Function Mutation / genetics
Male
Mycobacterium / immunology*
Mycobacterium Infections / genetics
Mycobacterium Infections / immunology
Mycobacterium Infections / microbiology
Pedigree
T-Box Domain Proteins / chemistry
T-Box Domain Proteins / deficiency
T-Box Domain Proteins / genetics
T-Box Domain Proteins / metabolism*
T-Lymphocytes, Helper-Inducer / immunology
Transcriptome / genetics

Substances

Chromatin
T-Box Domain Proteins
T-box transcription factor TBX21
Interferon-gamma

Abstract

Publication types

MeSH terms

Substances

Grants and funding