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

Nat Med. 2021 Sep;27(9):1646-1654. doi: 10.1038/s41591-021-01388-5. Epub 2021 Jun 28.


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 CD56bright 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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmunity / genetics*
  • Autoimmunity / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • CD56 Antigen / genetics
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Child
  • Humans
  • Immune Checkpoint Inhibitors / adverse effects
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy / adverse effects
  • Interleukin-23 / genetics
  • Interleukin-6 / genetics
  • Intraepithelial Lymphocytes / immunology
  • Intraepithelial Lymphocytes / pathology
  • Male
  • Mycobacterium tuberculosis / pathogenicity
  • Neoplasms / complications
  • Neoplasms / drug therapy
  • Neoplasms / mortality
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics*
  • Programmed Cell Death 1 Receptor / deficiency
  • Programmed Cell Death 1 Receptor / genetics*
  • STAT3 Transcription Factor / genetics*
  • Tuberculosis / genetics
  • Tuberculosis / immunology*
  • Tuberculosis / mortality


  • CD56 Antigen
  • Immune Checkpoint Inhibitors
  • Interleukin-23
  • Interleukin-6
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • RORC protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human