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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
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
BioProject PRJNA1013809

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

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