NFATc1 regulates PD-1 expression upon T cell activation.
PD-1 is a transmembrane protein involved in the regulation of immunological tolerance. Multiple studies have reported an association between high levels of PD-1 expressed on T cell surfaces and exhaustion in lymphocyte populations when challenged by chronic viral infections, such as HIV. By using model systems consisting of murine EL4 cells, which constitutively express PD-1, and primary murine CD8 T cells that express PD-1 upon T cell stimulation, we have identified two tissue-specific hypersensitive sites at the 5' CR of the PD-1 locus. Gene reporter assays in CD8 T cells have shown that one of these sites has robust transcriptional activity in response to cell stimulation. Cell treatment with the calcineurin inhibitor cyclosporine A or a NFAT-specific inhibitor led to a sharp reduction in PD-1 expression in the constitutive and inducible systems. Furthermore, analysis of this region by chromatin immunoprecipitation assay revealed NFATc1 binding associated with gene activation in EL4 and primary CD8 T cells. Mutation of the NFATc1 binding site in PD-1 reporter constructs resulted in a complete loss of promoter activity. Together, these results demonstrate that PD-1 gene regulation occurs in part via the recruitment of NFATc1 to a novel regulatory element at the pdcd1 locus and provides the molecular mechanism responsible for the induction of PD-1 in response to T cell stimulation.
Oestreich
Kenneth J
KJ
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Yoon
Hyesuk
H
Ahmed
Rafi
R
Boss
Jeremy M
JM
D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017124:Conserved Sequence / Q000276:immunology; D003850:Deoxyribonuclease I / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D005819:Genetic Markers; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D012045:Regulatory Sequences, Nucleic Acid / Q000276:immunology; D014158:Transcription, Genetic
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D005819:Genetic Markers; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D003850:Deoxyribonuclease I
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