PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response

JCI Insight. 2021 Dec 22;6(24):e146701. doi: 10.1172/jci.insight.146701.


A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19-related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared with healthy controls. Plasma levels of IL-1β, IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1-targeting miR-15-5p, in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post-COVID-19 immune abnormalities; indeed, we also noted an increased T cell-mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post-COVID-19 immune abnormalities and stimulates an anti-SARS-CoV-2 immune response.

Keywords: Anergy; COVID-19; Immunology; Immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / immunology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • COVID-19 / complications*
  • COVID-19 / immunology
  • Case-Control Studies
  • Cytokines / drug effects
  • Cytokines / immunology*
  • DNA Methylation
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology*
  • Immunophenotyping
  • In Vitro Techniques
  • Interleukin 1 Receptor Antagonist Protein / drug effects
  • Interleukin 1 Receptor Antagonist Protein / immunology
  • Interleukin-1beta / drug effects
  • Interleukin-1beta / immunology
  • Interleukin-8 / drug effects
  • Interleukin-8 / immunology
  • Male
  • MicroRNAs / metabolism
  • Middle Aged
  • Post-Acute COVID-19 Syndrome
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology*
  • Promoter Regions, Genetic
  • SARS-CoV-2 / immunology*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology*


  • B7-H1 Antigen
  • CXCL8 protein, human
  • Cytokines
  • IL1B protein, human
  • IL1RN protein, human
  • Immune Checkpoint Inhibitors
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • Interleukin-8
  • MIRN15 microRNA, human
  • MicroRNAs
  • Programmed Cell Death 1 Receptor