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

Seigo Terawaki, Shunsuke Chikuma, Shiro Shibayama, Tamon Hayashi, Takao Yoshida, Taku Okazaki, Tasuku Honjo

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2772-2779
Number of pages8
JournalJournal of Immunology
Volume186
Issue number5
DOIs
Publication statusPublished - 2011 Mar 1
Externally publishedYes

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Cellular Immunity
Cell Death
T-Lymphocytes
Response Elements
5' Flanking Region
Immunotherapy
Immunity
Neoplasms
Maintenance
Cell Line
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. / Terawaki, Seigo; Chikuma, Shunsuke; Shibayama, Shiro; Hayashi, Tamon; Yoshida, Takao; Okazaki, Taku; Honjo, Tasuku.

In: Journal of Immunology, Vol. 186, No. 5, 01.03.2011, p. 2772-2779.

Research output: Contribution to journalArticle

Terawaki, Seigo ; Chikuma, Shunsuke ; Shibayama, Shiro ; Hayashi, Tamon ; Yoshida, Takao ; Okazaki, Taku ; Honjo, Tasuku. / IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. In: Journal of Immunology. 2011 ; Vol. 186, No. 5. pp. 2772-2779.
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