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T cell homeostasis and antitumor function require the Na+-K+-ATPase

ABSTRACT: 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).

ORGANISM(S): Mus musculus

PROVIDER: GSE242525 | GEO | 2023/10/05

REPOSITORIES: GEO

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Project description:The Na/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na/K-ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, we compared mice expressing the naturally resistant Na/K-ATPase α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2 and β1 protein content remained unchanged, and the cardiac Na/K-ATPase dose-response curve to ouabain shifted to the left as expected. In males aged 3–6 months, increased α1 sensitivity to CTS resulted in a significant increase of cardiac carbonylated protein content, suggesting that ROS production was elevated. A moderate but significant increase of about 15% of the heart-weight-to-tibia-length ratio, accompanied by an increase of myocyte cross-sectional area was detected. Echocardiographic analyses did not reveal any change in cardiac function, and there was no fibrosis or re-expression of the fetal gene program. RNA sequencing analysis indicated that pathways related to energy metabolism were upregulated, while those related to extracellular matrix organization were downregulated. Consistent with a functional role of the latter, an angiotensin-II challenge that triggered fibrosis in the α1r/rα2s/s mouse failed to do so in the α1s/sα2s/s. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions.

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T cell homeostasis and antitumor function require the Na+-K+-ATPase

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