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Ogishi, Masato; Yang, Rui; Aytekin, Caner; Langlais, David; Bourgey, Mathieu; Khan, Taushif; Ali, Fatima Al; Rahman, Mahbuba; Delmonte, Ottavia M; Chrabieh, Maya; Zhang, Peng; Gruber, Conor; Pelham, Simon J; Spaan, András N; Rosain, Jérémie; Lei, Wei-Te; Drutman, Scott; Hellmann, Matthew D; Callahan, Margaret K; Adamow, Matthew; Wong, Phillip; Wolchok, Jedd D; Rao, Geetha; Ma, Cindy S; Nakajima, Yuka; Yaguchi, Tomonori; Chamoto, Kenji; Williams, Samuel C; Emile, Jean-Francois; Rozenberg, Flore; Glickman, Michael S; Rapaport, Franck; Kerner, Gaspard; Allington, Garrett; Tezcan, Ilhan; Cagdas, Deniz; Hosnut, Ferda O; Dogu, Figen; Ikinciogullari, Aydan; Rao, V Koneti; Kainulainen, Leena; Béziat, Vivien; Bustamante, Jacinta; Vilarinho, Silvia; Lifton, Richard P; Boisson, Bertrand; Abel, Laurent; Bogunovic, Dusan; Marr, Nico; Notarangelo, Luigi D; Tangye, Stuart G; Honjo, Tasuku; Gros, Philippe; Boisson-Dupuis, Stéphanie; Casanova, Jean-Laurent
Nature medicine, 09/2021, Volume: 27, Issue: 9Journal Article
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 CD56 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.
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