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Series GSE242525 Query DataSets for GSE242525
Status Public on Oct 05, 2023
Title T cell homeostasis and antitumor function require the Na+-K+-ATPase
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary The cancer-killing activity of T cells is often compromised within tumors, allowing disease progression. We previously found that intratumoral elevations in extracellular K+ constrain T cell antitumor function. Despite the relevance of K+abundance for T cell antitumor function and the importance of ion gradients for cellular physiology broadly, our understanding of T cell K+ transporters remains rudimentary7,8. Here, we report that the Na+-K+-ATPase is required for T cell quiescence, memory formation, and antitumor activity. Deletion of Atp1a1, the catalytic alpha subunit of the Na+-K+-ATPase, in CD8+ T cells induced constitutive activity in TCR, Akt-mTOR, and MAPK/ Erk signaling pathways. This state of tonic signal transduction was reflected in the acquisition of co-inhibitory surface receptors and terminal differentiation in T cells following Atp1a1 deletion. Mechanistically, we found that the Na+-K+-ATPase functions to support ROS homeostasis as its disruption produced ROS accumulation and the addition of antioxidants prevented the accelerated differentiation and acquisition of co-inhibitory receptors in T cells lacking Atp1a1. The in vivo behavior of T cells lacking Atp1a1 was also consistent with tonic signal transduction and stimulation-induced terminal differentiation. T cells lacking Atp1a1 could not achieve proliferative burst or form memory following pathogen challenge or perform tumor destruction in a syngeneic model of orthotopic murine melanoma. These results highlight the fundamental but underappreciated importance of monovalent ion transporters in T cell biology and have translational implications for the ongoing development of immune checkpoint blockade and T cell transfer therapies (i.e. CAR, TCR, TIL).
 
Overall design Comparitive gene expression profiling of RNA-seq data for C57BL/6 murine CD8+ T cells electroporated with CRISPR-Cas9 molecules complexed to sgRNAs encoding Atp1a1 specific or scramble sequences
 
Contributor(s) Robert E, Camille C
Citation(s) 38063845
Submission date Sep 07, 2023
Last update date Jan 16, 2024
Contact name Robert Eil
E-mail(s) eil.lab.research@gmail.com, eillab@ohsu.edu
Organization name Oregon Health and Science University
Street address 3266 SW Research Drive
City Portland
State/province Oregon
ZIP/Postal code 97239-3098
Country USA
 
Platforms (1)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
Samples (6)
GSM7765131 CD8+ T cell ATP1a1 KO No stim Rep1
GSM7765132 CD8+ T cell ATP1a1 KO No stim Rep2
GSM7765133 CD8+ T cell ATP1a1 KO No stim Rep3
Relations
BioProject PRJNA1013809

Download family Format
SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE242525_RAW.tar 20.0 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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