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


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)-gamma upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-gamma production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vdelta2(+) gammadelta T, mucosal-associated invariant T and CD56(bright) natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORgammaT(+) CD4(-)CD8(-) double-negative alphabeta 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 RORgammaT 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.

Type Journal
ISBN 1546-170X (Electronic) 1078-8956 (Linking)
Authors Ogishi, M.; Yang, R.; Aytekin, C.; Langlais, D.; Bourgey, M.; Khan, T.; Ali, F. A.; Rahman, M.; Delmonte, O. M.; Chrabieh, M.; Zhang, P.; Gruber, C.; Pelham, S. J.; Spaan, A. N.; Rosain, J.; Lei, W. T.; Drutman, S.; Hellmann, M. D.; Callahan, M. K.; Adamow, M.; Wong, P.; Wolchok, J. D.; Rao, G.; Ma, C. S.; Nakajima, Y.; Yaguchi, T.; Chamoto, K.; Williams, S. C.; Emile, J. F.; Rozenberg, F.; Glickman, M. S.; Rapaport, F.; Kerner, G.; Allington, G.; Tezcan, I.; Cagdas, D.; Hosnut, F. O.; Dogu, F.; Ikinciogullari, A.; Rao, V. K.; Kainulainen, L.; Beziat, V.; Bustamante, J.; Vilarinho, S.; Lifton, R. P.; Boisson, B.; Abel, L.; Bogunovic, D.; Marr, N.; Notarangelo, L. D.; Tangye, S. G.; Honjo, T.; Gros, P.; Boisson-Dupuis, S.; Casanova, J. L.
Responsible Garvan Author A/Prof Cindy Ma
Published Date 2021-09-30
Published Volume 27
Published Issue 9
Published Pages 1646-1654
Status Published in-print
DOI 10.1038/s41591-021-01388-5
URL link to publisher's version