Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria PMID: 33296702

RQC and Longevity Regulation

2026-09-03

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.

Rui Yang ¹ , Federico Mele ² , Lisa Worley ³ , David Langlais ⁴ , Jérémie Rosain ⁵ , Ibithal Benhsaien ⁶ , Houda Elarabi ⁷ , Carys A Croft ⁸ , Jean-Marc Doisne ⁹ , Peng Zhang ¹⁰ , Marc Weisshaar ¹¹ , David Jarrossay ² , Daniela Latorre ¹¹ , Yichao Shen ¹⁰ , Jing Han ¹⁰ , Masato Ogishi ¹⁰ , Conor Gruber ¹² , Janet Markle ¹⁰ , Fatima Al Ali ¹³ , Mahbuba Rahman ¹³ , Taushif Khan ¹³ , Yoann Seeleuthner ⁵ , Gaspard Kerner ⁵ , Lucas T Husquin ¹⁴ , Julia L Maclsaac ¹⁵ , Mohamed Jeljeli ¹⁶ , Abderrahmane Errami ¹⁷ , Fatima Ailal ⁶ , Michael S Kobor ¹⁵ , Carmen Oleaga-Quintas ⁵ , Manon Roynard ⁵ , Mathieu Bourgey ¹⁸ , Jamila El Baghdadi ¹⁹ , Stéphanie Boisson-Dupuis ²⁰ , Anne Puel ²⁰ , Fréderic Batteux ¹⁶ , Flore Rozenberg ²¹ , Nico Marr ²² , Qiang Pan-Hammarström ²³ , Dusan Bogunovic ¹² , Lluis Quintana-Murci ²⁴ , Thomas Carroll ²⁵ , Cindy S Ma ³ , Laurent Abel ²⁰ , Aziz Bousfiha ⁶ , James P Di Santo ⁹ , Laurie H Glimcher ²⁶ , Philippe Gros ²⁷ , Stuart G Tangye ³ , Federica Sallusto ²⁸ , Jacinta Bustamante ²⁹ , Jean-Laurent Casanova ³⁰

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.