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

Masato Ogishi, Rui Yang, Caner Aytekin, David Langlais, Mathieu Bourgey, Taushif Khan, Fatima Al Ali, Mahbuba Rahman, Ottavia M. Delmonte, Maya Chrabieh, Peng Zhang, Conor Gruber, Simon J. Pelham, András N. Spaan, Jérémie Rosain, Wei Te Lei, Scott Drutman, Matthew D. Hellmann, Margaret K. Callahan, Matthew AdamowPhillip Wong, Jedd D. Wolchok, Geetha Rao, Cindy S. Ma, Yuka Nakajima, Tomonori Yaguchi, Kenji Chamoto, Samuel C. Williams, Jean Francois Emile, Flore Rozenberg, Michael S. Glickman, Franck Rapaport, Gaspard Kerner, Garrett Allington, Ilhan Tezcan, Deniz Cagdas, Ferda O. Hosnut, Figen Dogu, Aydan Ikinciogullari, V. Koneti Rao, Leena Kainulainen, Vivien Béziat, Jacinta Bustamante, Silvia Vilarinho, Richard P. Lifton, Bertrand Boisson, Laurent Abel, Dusan Bogunovic, Nico Marr, Luigi D. Notarangelo, Stuart G. Tangye, Tasuku Honjo, Philippe Gros, Stéphanie Boisson-Dupuis, Jean Laurent Casanova

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


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+ CD4CD8 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.

Original languageEnglish
Pages (from-to)1646-1654
Number of pages9
JournalNature Medicine
Issue number9
StatePublished - Sep 2021


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