IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity.
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.
Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida-konoe, Sakyo-Ku, Kyoto 606-8501, Japan.
Seigo
S
Terawaki
Shunsuke
S
Chikuma
Shiro
S
Shibayama
Tamon
T
Hayashi
Takao
T
Yoshida
Taku
T
Okazaki
Tasuku
T
Honjo
D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism / Q000502:physiology; D016898:Interferon-alpha / Q000502:physiology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology; D050436:Regulatory Elements, Transcriptional / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000276:immunology*
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; C494228:Isgf3g protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell