Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a pediatric patient

The pathophysiology of adverse events to PD-1 blockade immunotherapy, 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 expression or respond to PD-1-mediated suppression. The patient's lymphocytes barely produced interferon (IFN)-gamma upon mycobacterial stimuli, similar to patients with inborn errors of IFN-gamma production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vdelta2+ gamma-delta T, MAIT, and CD56bright NK 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 (DN) alpha-beta T cells, similar to patients with STAT3 gain-of-function (GOF) mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines 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 self-tolerance and protective immunity, while providing a basis for improving clinical management of adverse events following PD-1 blockade.