Notch signaling regulates PD-1 expression during CD8(+) T-cell activation.
Programmed cell death 1 (PD-1) is an inhibitory receptor involved in T-cell activation, tolerance and exhaustion. Little is known on how the expression of PD-1 is controlled during T-cell activation. Recent studies demonstrated that NFATc1 and IRF9 regulate Pdcd1 (PD-1) transcription and that T-bet acts as a transcriptional repressor. In this study, we have investigated the role of the Notch signaling pathway in PD-1 regulation. Using specific inhibitors of the Notch signaling pathway, we showed decreased PD-1 expression and inhibition of Pdcd1 transcription by activated CD8(+) T cells. Chromatin immunoprecipitation further showed occupancy of the Pdcd1 promoter with RBPJk and Notch1 intracellular domain at RBPJk-binding sites. Our results identify the Notch signaling pathway as an important regulator of PD-1 expression by activated CD8(+) T cells.
Maisonneuve-Rosemont Hospital Research Center, University of Montreal, Montréal, Quebec, Canada.
Mélissa
M
Mathieu
Natacha
N
Cotta-Grand
Jean-François
JF
Daudelin
Paméla
P
Thébault
Nathalie
N
Labrecque
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020218:Response Elements / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology
D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D050778:NFATC Transcription Factors; D061026:Programmed Cell Death 1 Receptor; D051881:Receptor, Notch1; C494005:Nfatc1 protein, mouse; C497762:Notch1 protein, mouse; C491383:Pdcd1 protein, mouse; C494228:Isgf3g protein, mouse