Type I interferon promotes PD-1 transcription and limits the duration of T cell-mediated immunity (63.24)

Abstract PD-1 is a co-receptor 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 analyzed a conserved 5’-flanking region of the PD-1 gene, and identified a putative interferon-stimulation response element (ISRE), which was responsible for PD-1 transcription in the 2B4.11 T-cell line. Consistent with this finding, activation by interferon (IFN) alpha enhanced both the induction and maintenance of PD-1 expression on TCR-engaged primary mouse T cells through an association of interferon-responsive factor-9 (IRF9) to the ISRE. Indeed, PD-1 expression on antigen-specific CD8+ T cells was augmented by IFN alpha in vivo. We also demonstrated that IFN alpha administration in combination with PD-1 blockade in tumor-bearing mice effectively augmented the anti-tumor immunity. Thus 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 interferon-mediated PD-1 transcription.