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

S Terawaki, S Chikuma, S Shibayama… - The Journal of …, 2011 - journals.aai.org
S Terawaki, S Chikuma, S Shibayama, T Hayashi, T Yoshida, T Okazaki, T Honjo
The Journal of Immunology, 2011journals.aai.org
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 …
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.
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