Minimal PD-1 expression in mouse and human NK cells under diverse conditions

J Clin Invest. 2020 Jun 1;130(6):3051-3068. doi: 10.1172/JCI133353.


PD-1 expression is a hallmark of both early antigen-specific T cell activation and later chronic stimulation, suggesting key roles in both naive T cell priming and memory T cell responses. Although significant similarities exist between T cells and NK cells, there are critical differences in their biology and functions reflecting their respective adaptive and innate immune effector functions. Expression of PD-1 on NK cells is controversial despite rapid incorporation into clinical cancer trials. Our objective was to stringently and comprehensively assess expression of PD-1 on both mouse and human NK cells under multiple conditions and using a variety of readouts. We evaluated NK cells from primary human tumor samples, after ex vivo culturing, and from multiple mouse tumor and viral models using flow cytometry, quantitative reverse-transcriptase PCR (qRT-PCR), and RNA-Seq for PD-1 expression. We demonstrate that, under multiple conditions, human and mouse NK cells consistently lack PD-1 expression despite the marked upregulation of other activation/regulatory markers, such as TIGIT. This was in marked contrast to T cells, which were far more prominent within all tumors and expressed PD-1. These data have important implications when attempting to discern NK from T cell effects and to determine whether PD-1 targeting can be expected to have direct effects on NK cell functions.

Keywords: Immunology; Immunotherapy; NK cells.

Publication types

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

MeSH terms

  • Animals
  • Gene Expression Regulation / immunology*
  • Humans
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / pathology
  • Mice
  • Mice, Knockout
  • Programmed Cell Death 1 Receptor / immunology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology


  • PDCD1 protein, human
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor