ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/071/SRR21387171/SRR21387171_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/075/SRR21387175/SRR21387175_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/077/SRR21387177/SRR21387177_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/079/SRR21387179/SRR21387179_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/067/SRR21387167/SRR21387167_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/072/SRR21387172/SRR21387172_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/065/SRR21387165/SRR21387165_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/069/SRR21387169/SRR21387169_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/081/SRR21387181/SRR21387181_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/080/SRR21387180/SRR21387180_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/070/SRR21387170/SRR21387170_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/064/SRR21387164/SRR21387164_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/068/SRR21387168/SRR21387168_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/076/SRR21387176/SRR21387176_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/068/SRR21387168/SRR21387168_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/074/SRR21387174/SRR21387174_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/071/SRR21387171/SRR21387171_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/080/SRR21387180/SRR21387180_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/079/SRR21387179/SRR21387179_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/065/SRR21387165/SRR21387165_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/081/SRR21387181/SRR21387181_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/073/SRR21387173/SRR21387173_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/066/SRR21387166/SRR21387166_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/078/SRR21387178/SRR21387178_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/077/SRR21387177/SRR21387177_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/074/SRR21387174/SRR21387174_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/075/SRR21387175/SRR21387175_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/072/SRR21387172/SRR21387172_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/070/SRR21387170/SRR21387170_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/064/SRR21387164/SRR21387164_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/078/SRR21387178/SRR21387178_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/076/SRR21387176/SRR21387176_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/073/SRR21387173/SRR21387173_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/069/SRR21387169/SRR21387169_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/067/SRR21387167/SRR21387167_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/066/SRR21387166/SRR21387166_1.fastq.gzprimaryOK200GenomicsSharpe, Immunology, Harvard Medical Schoolhttps://www.ebi.ac.uk/ena/browser/view/PRJNA875661Mus musculusT cell exhaustion is a state of CD8+ T cell dysfunction elicited by chronic exposure to antigen and inflammation, arises in both cancer and chronic viral infection. 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.xref:PubMed:39289557ENAHITS-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-ExonucleaseHITS-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-ExonucleasefalseDeletion of a state-specific PD-1 enhancer modulates exhausted T cell fate and function [ATAC-seq]Deletion of a state-specific PD-1 enhancer modulates exhausted T cell fate and function [ATAC-seq]2025-09-242024-07-31PRJNA875661GSE2125061009039289557