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Autor(en) / Beteiligte

Titel

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

Ist Teil von

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

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.

Sprache: Englisch
Identifikatoren: ISSN: 1078-8956
eISSN: 1546-170X
DOI: 10.1038/s41591-021-01388-5
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8446316

Format: –
Schlagworte: Apoptosis, Autoimmunity, Autoimmunity - genetics, Autoimmunity - immunology, CD4 antigen, CD4-Positive T-Lymphocytes - immunology, CD4-Positive T-Lymphocytes - pathology, CD56 Antigen - genetics, CD8 antigen, CD8-Positive T-Lymphocytes - immunology, CD8-Positive T-Lymphocytes - pathology, Cell death, Child, Cytokines, Depletion, Disease management, Humans, Immune Checkpoint Inhibitors - adverse effects, Immune Checkpoint Inhibitors - therapeutic use, Immunological tolerance, Immunotherapy - adverse effects, Interferon, Interleukin 23, Interleukin 6, Interleukin-23 - genetics, Interleukin-6 - genetics, Intraepithelial Lymphocytes - immunology, Intraepithelial Lymphocytes - pathology, Leukocytes, Lymphocytes, Lymphocytes T, Male, Monocytes, Mucosa, Mutation, Mycobacterium tuberculosis - pathogenicity, Neoplasms - complications, Neoplasms - drug therapy, Neoplasms - mortality, Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics, Patients, PD-1 protein, Phenotypes, Programmed Cell Death 1 Receptor - deficiency, Programmed Cell Death 1 Receptor - genetics, Stat3 protein, STAT3 Transcription Factor - genetics, Tuberculosis, Tuberculosis - genetics, Tuberculosis - immunology, Tuberculosis - mortality, γ-Interferon

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