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Masato Ogishi, Rui Yang, Caner Aytekin, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova, Inherited human PD-1 deficiency underlies tuberculosis and autoimmunity, The Journal of Immunology, Volume 206, Issue 1_Supplement, May 2021, Page 52.10, https://doi.org/10.4049/jimmunol.206.Supp.52.10
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Abstract
The pathogenesis of adverse reactions to PD-1 blockade immunotherapy, including tuberculosis (TB) and autoimmunity, remains poorly characterized. Here, we study a patient with inherited PD-1 deficiency who suffered from TB and died of pulmonary autoimmunity. The patient’s leukocytes displayed no PD-1 expression and did not respond to PD-1-mediated suppression. Similar to various inborn errors of immunity impairing interferon (IFN)-γ production and underlying TB, the patient’s lymphocytes poorly produced IFN-γ in response to mycobacterial stimuli owing to both the depletion of multiple IFN-γ-producing T and NK lymphocyte subsets, including Vδ2+ γδ T, MAIT, and CD56bright NK lymphocytes, and dysfunction of residual T lymphocytes. Another set of inborn errors, including STAT3 gain-of-function (GOF) mutations, trigger an expansion of CD4−CD8− double-negative (DN) αβ T cells and underlie lymphoproliferative autoimmunity. Remarkably, the patient displayed hepatosplenomegaly and expansion of total, activated, and RORγT+ DN αβ T cells, as observed in PD-1-deficient mice and cancer patients with PD-1 blockade. Mechanistically, the patient’s myeloid cells produced excessive amounts of STAT3-activating cytokines IL-6 and IL-23 upon stimulation with lipopolysaccharide. Overall, inherited human PD-1 deficiency underlies TB through undermining IFN-γ production by T and NK lymphocytes and lymphoproliferative autoimmunity through over-activating STAT3.
