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The co-inhibitory receptor PD-1 plays a key role in mediating exhaustion, but complete ablation of PD-1 by gene knock-out leads to deeper functional deficits and poor T cell survival. We hypothesized that an intermediate level of PD-1 expression may confer an improved balance of exhausted CD8+ T cell functionality, so we deleted an exhaustion-associated enhancer of PD-1 which indeed resulted in a reduced expression level. We compared EnhDel, WT and PD-1 KO T cells using single-cell RNA-Seq and found that PD-1 KO but not EnhDel cells are strongly biased towards the terminally exhausted subset. EnhDel cells also uniquely enrich for effector-associated genes and gene signatures. However, all three genotypes (EnhDel, WT and PD-1 KO) exhibit a similar chromatin accessibility landscape by ATAC-Seq, controlling for exhausted subset. These data suggest that tuning of PD-1 expression may uniquely permit the maintenance of an “effector” transcriptional profile in exhausted CD8+ T cells. Overall design: Enhancer-deleted and PD-1 KO P14+ cells, or enhancer-deleted and wildtype P14+ cells, were co-transferred into recipient animals (n = 15-30) at a 75:25 or 50:50 ratio, respectively. Recipients were infected with LCMV Clone 13. At day 30, spleens were pooled into two biological replicates and transferred CD8+ T cells were isolated with magnetic enrichment. Progenitor and terminally-exhausted subsets for each genotype were isolated with flow-assisted sorting, and samples were processed for ATAC-Seq."],"tag":["xref:PubMed:39289557"],"repository":["ENA"],"description_synonyms":["HITS-CLIP, High Throughput Sequencing of RNA Isolated by Crosslinking Immunoprecipitation, ChIP-Chip, SLEB2, Chromatin Immuno-precipitation, Cross Linking and Immunoprecipitation Followed by Deep Sequencing, l17, ChIP Sequencing, CLIP-Seq, function, Assay for Transposase-Accessible Chromatin Using Sequencing, ChIP-PET, ChIP-Exo, RPL23, rpl17a, pd-1, CT43, Chromatin Immunoprecipitation Sequencing-Chip, Tex cell, High-Throughput Sequencing of RNA Isolated by Crosslinking Immunoprecipitation, PD1, INSDC_feature:regulatory, PD-1, Ly101, Chromatin Immunoprecipitation Sequencing Chip, Chromatin Immuno precipitation Sequencing, ATAC-seq assay, FATE, ChIP, Chromatin Immunoprecipitation Paired End Tag, ATAC-seq, Chromatin Immuno Precipitation Paired End Tag, Cross-Linking and Immunoprecipitation Followed by Deep Sequencing, 60S ribosomal protein L23, Chromatin Immunoprecipitation, rpl23, Chromatin Immuno-precipitation Sequencing, ChIP Exonuclease, ChIP-Seq, CD279, Sequencing, hPD-1, Assay for Transposase Accessible Chromatin Using Sequencing, Chromatin Immunoprecipitation Paired-End Tag, hPD-l, Pdc1, DEL, ChIA-PET., hSLE1, Chromatin Immuno-Precipitation Paired-End Tag, rpl17, ATAC-Seq, Chromatin Immunoprecipitation Sequencing-Chips, L17, ChIP-Exonuclease"],"name_synonyms":["HITS-CLIP, High Throughput Sequencing of RNA Isolated by Crosslinking Immunoprecipitation, ChIP-Chip, SLEB2, Chromatin Immuno-precipitation, Cross Linking and Immunoprecipitation Followed by Deep Sequencing, l17, ChIP Sequencing, CLIP-Seq, function, Assay for Transposase-Accessible Chromatin Using Sequencing, ChIP-PET, ChIP-Exo, RPL23, rpl17a, pd-1, CT43, Chromatin Immunoprecipitation Sequencing-Chip, Tex cell, High-Throughput Sequencing of RNA Isolated by Crosslinking Immunoprecipitation, PD1, INSDC_feature:regulatory, PD-1, Ly101, Chromatin Immunoprecipitation Sequencing Chip, Chromatin Immuno precipitation Sequencing, ATAC-seq assay, FATE, ChIP, Chromatin Immunoprecipitation Paired End Tag, ATAC-seq, Chromatin Immuno Precipitation Paired End Tag, Cross-Linking and Immunoprecipitation Followed by Deep Sequencing, 60S ribosomal protein L23, Chromatin Immunoprecipitation, rpl23, Chromatin Immuno-precipitation Sequencing, ChIP Exonuclease, ChIP-Seq, CD279, Sequencing, hPD-1, Assay for Transposase Accessible Chromatin Using Sequencing, Chromatin Immunoprecipitation Paired-End Tag, hPD-l, Pdc1, DEL, ChIA-PET., hSLE1, Chromatin Immuno-Precipitation Paired-End Tag, rpl17, ATAC-Seq, Chromatin Immunoprecipitation Sequencing-Chips, L17, ChIP-Exonuclease"],"additional_accession":[]},"is_claimable":false,"name":"Deletion of a state-specific PD-1 enhancer modulates exhausted T cell fate and function [ATAC-seq]","description":"Deletion of a state-specific PD-1 enhancer modulates exhausted T cell fate and function [ATAC-seq]","dates":{"last_updated":"2025-09-24","first_public":"2024-07-31"},"accession":"PRJNA875661","cross_references":{"GEO":["GSE212506"],"taxon":["10090"],"PubMed":["39289557"]}}