VNUT-mediated ATP release suppresses T helper 1 (T<sub>H</sub>1) cell differentiation via the P2X7R-JNK-FOXO3a-Eomes signaling cascade.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41417887.
- Also identified by DOI 10.1126/sciadv.adz7600 and PMC identifier 13142776.
- Licence recorded as CC BY-NC.
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Abstract
Extracellular ATP (eATP), a well-recognized danger signal and immune activator, is implicated in the activation, differentiation, and function of T cells, directly or indirectly. Yet, how T cells release ATP themselves and its effects remain poorly investigated. Here, we found vesicular nucleotide transporter (VNUT), critical for vesicular ATP storage/release, is highly expressed in T<sub>H</sub>1 cells and selectively restricts their differentiation and effector functions. Mechanistically, VNUT facilitates lysosomal ATP import and its extracellular release upon T cell receptor engagement. This eATP then activates the purinergic receptor P2X7R and downstream SRC kinase, triggering a signaling cascade involving heightened Ca<sup>2+</sup> influx and hyperphosphorylation of JNK and FOXO3a, which ultimately impairs Eomes-directed IFN-γ production in T<sub>H</sub>1 cells. Genetic/pharmacological of VNUT inhibition significantly potentiates T<sub>H</sub>1 effector functions against <i>Listeria</i> infection and transplanted tumors. These findings identify VNUT as a critical checkpoint in limiting T<sub>H</sub>1 immunity, coupling vesicular ATP transport to transcriptional control via the P2X7R-JNK-FOXO3a-Eomes axis, offering a target for treating infection and cancer.
Medical subject headings
- Receptors, Purinergic P2X7
- Adenosine Triphosphate
- Forkhead Box Protein O3
- Cell Differentiation
- Th1 Cells
- Signal Transduction
- Nucleotide Transport Proteins