ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/054/SRR21358054/SRR21358054.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/037/SRR21358037/SRR21358037.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/043/SRR21358043/SRR21358043.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/052/SRR21358052/SRR21358052.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/035/SRR21358035/SRR21358035.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/039/SRR21358039/SRR21358039.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/046/SRR21358046/SRR21358046.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/041/SRR21358041/SRR21358041.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/048/SRR21358048/SRR21358048.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/050/SRR21358050/SRR21358050.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/033/SRR21358033/SRR21358033.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/047/SRR21358047/SRR21358047.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/055/SRR21358055/SRR21358055.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/044/SRR21358044/SRR21358044.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/056/SRR21358056/SRR21358056.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/049/SRR21358049/SRR21358049.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/042/SRR21358042/SRR21358042.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/045/SRR21358045/SRR21358045.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/038/SRR21358038/SRR21358038.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/053/SRR21358053/SRR21358053.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/051/SRR21358051/SRR21358051.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/034/SRR21358034/SRR21358034.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/040/SRR21358040/SRR21358040.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR213/036/SRR21358036/SRR21358036.fastq.gzprimaryOK200GenomicsSharpe, Immunology, Harvard Medical Schoolhttps://www.ebi.ac.uk/ena/browser/view/PRJNA875151Mus musculusxref:PubMed:39289557T 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, PD-1 KO and WT P14+ CD8+ T cells were isolated from donor mice, mixed at a 33:33:33 ratio, and transferred to GFP+ recipient mice (n = 5). Recipients were infected with LCMV Clone 13. Transferred CD8+ T cells were isolated from spleens at day 29 of infection, then pooled into two biological replicates. Genotypes (Enhancer-deleted, PD-1 KO, WT) were then isolated by sorting and processed for scRNA-Seq.ENAfalseDeletion of a state-specific PD-1 enhancer modulates exhausted T cell fate and function [scRNA-seq]Deletion of a state-specific PD-1 enhancer modulates exhausted T cell fate and function [scRNA-seq]2025-09-242024-07-31PRJNA875151GSE2123791009039289557