IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity

J Immunol. 2011 Mar 1;186(5):2772-9. doi: 10.4049/jimmunol.1003208. Epub 2011 Jan 24.


Programmed cell death-1 (PD-1) is an inhibitory coreceptor for T lymphocytes that provides feedback inhibition of T cell activation. Although PD-1's expression on T cells is known to be activation dependent, the factors that determine the timing, intensity, and duration of PD-1 expression in immune reactions are not fully understood. To address this question, we performed a fine mapping analysis of a conserved 5'-flanking region of the PD-1 gene and identified a putative IFN stimulation response element, which was responsible for PD-1 transcription in the 2B4.11 T cell line. Consistent with this finding, activation by IFN-α enhanced both the induction and maintenance of PD-1 expression on TCR-engaged primary mouse T cells through an association IFN-responsive factor 9 (IRF9) to the IFN stimulation response element. Furthermore, PD-1 expression on Ag-specific CD8(+) T cells was augmented by IFN-α in vivo. We propose that strong innate inflammatory responses promote primary T cell activation and their differentiation into effector cells, but also cause an attenuated T cell response in sustained immune reactions, at least partially through type I IFN-mediated PD-1 transcription. Based on this idea, we demonstrate that IFN-α administration in combination with PD-1 blockade in tumor-bearing mice effectively augments the antitumor immunity, and we propose this as a novel and rational approach for cancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / biosynthesis
  • Antigens, Surface / genetics*
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / biosynthesis
  • Apoptosis Regulatory Proteins / genetics*
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Humans
  • Immunity, Cellular* / genetics
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / physiology
  • Interferon-alpha / physiology*
  • Interferon-alpha / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Antigen, T-Cell / physiology
  • Regulatory Elements, Transcriptional / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism*
  • Transcription, Genetic / immunology*


  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha
  • Isgf3g protein, mouse
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell