Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.

Nat Med. 2021 Jun 28. doi: 10.1038/s41591-021-01388-5. | PubMed

Masato Ogishi^1,2, Rui Yang³, Caner Aytekin⁴, David Langlais⁵, Mathieu Bourgey⁶, Taushif Khan⁷, Fatima Al Ali⁷, Mahbuba Rahman⁷, Ottavia M Delmonte⁸, Maya Chrabieh^9,10, Peng Zhang³, Conor Gruber^11,12,13,14, Simon J Pelham³, András N Spaan³, Jérémie Rosain^9,10, Wei-Te Lei³, Scott Drutman³, Matthew D Hellmann^15,16, Margaret K Callahan^15,16, Matthew Adamow^17,18, Phillip Wong¹⁷, Jedd D Wolchok^15,16,18,19, Geetha Rao²⁰, Cindy S Ma^20,21, Yuka Nakajima²², Tomonori Yaguchi²², Kenji Chamoto²², Samuel C Williams^23,24, Jean-Francois Emile²⁵, Flore Rozenberg²⁶, Michael S Glickman²⁷, Franck Rapaport³, Gaspard Kerner^9,10, Garrett Allington^28,29,30, Ilhan Tezcan³¹, Deniz Cagdas³¹, Ferda O Hosnut³², Figen Dogu³³, Aydan Ikinciogullari³³, V Koneti Rao³⁴, Leena Kainulainen³⁵, Vivien Béziat^3,9,10, Jacinta Bustamante^3,9,10,36, Silvia Vilarinho^28,29,30, Richard P Lifton^28,37, Bertrand Boisson^3,9,10, Laurent Abel^3,9,10, Dusan Bogunovic^11,12,13,14, Nico Marr^7,38, Luigi D Notarangelo⁸, Stuart G Tangye^20,21, Tasuku Honjo²², Philippe Gros^39,40, Stéphanie Boisson-Dupuis^41,42,43, Jean-Laurent Casanova^44,45,46,47

1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA. mogishi@rockefeller.edu.
2. The David Rockefeller Graduate Program, Rockefeller University, New York, NY, USA. mogishi@rockefeller.edu.
3. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.
4. Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.
5. Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
6. McGill University Genome Center, Montreal, Quebec, Canada.
7. Department of Immunology, Research Branch, Sidra Medicine, Doha, Qatar.
8. Immune Deficiency Genetics Section, Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
9. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
10. University of Paris, Imagine Institute, Paris, France.
11. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
12. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
13. The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
14. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
15. Department of Medicine, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
16. Weill Cornell Medicine, New York, NY, USA.
17. Immune Monitoring Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
18. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
19. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
20. Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
21. St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, New South Wales, Australia.
22. Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
23. Laboratory of Investigative Dermatology, Rockefeller University, New York, NY, USA.
24. Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA.
25. Department of Pathology, Assistance Publique-Hôpitaux de Paris, Ambroise Paré Hospital, Boulogne-Billancourt, France.
26. Department of Virology, Cochin Hospital, University of Paris, Paris, France.
27. Immunology Program, Sloan Kettering Institute, New York, NY, USA.
28. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
29. Section of Digestive Diseases, Departments of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
30. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
31. Department of Pediatric Immunology, Hacettepe University Medical Faculty, Ankara, Turkey.
32. Department of Pediatric Gastroenterology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.
33. Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey.
34. Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
35. Department of Pediatrics and Department of Medicine, Turku University Hospital, Turku, Finland.
36. Study Center of Immunodeficiencies, Necker Hospital for Sick Children, Paris, France.
37. Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
38. College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
39. McGill Research Centre on Complex Traits, Montreal, Quebec, Canada.
40. Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
41. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA. stbo603@rockefeller.edu.
42. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France. stbo603@rockefeller.edu.
43. University of Paris, Imagine Institute, Paris, France. stbo603@rockefeller.edu.
44. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA. casanova@rockefeller.edu.
45. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France. casanova@rockefeller.edu.
46. University of Paris, Imagine Institute, Paris, France. casanova@rockefeller.edu.
47. Howard Hughes Medical Institute, New York, NY, USA. casanova@rockefeller.edu.

Abstract

The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient's lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2+ γδ T, mucosal-associated invariant T and CD56bright natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT+ CD4-CD8- double-negative αβ T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.

Presented By Masato Ogishi | ORCID iD