J Immunol. 2026 Nov 2;215(11):vkag282. doi: 10.1093/jimmun/vkag282.
ABSTRACT
Natural killer (NK) cell effector function requires coordinated receptor signaling, cytotoxic granule release, and metabolic fitness. V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint implicated in immune regulation, but its role in NK cell biology remains incompletely defined. Using VISTA-knockout (VKO) and wild-type mice, murine EO771 mammary tumor-bearing mice, and peripheral blood NK cells from human healthy controls and non-small cell lung cancer patients, we examined how VISTA expression or deficiency shapes NK cell phenotype and function. VISTA was detected on a subset of murine NK cells with an activated phenotype. In contrast, systemic VISTA deficiency expanded splenic NK cell numbers but produced phenotypic activation with impaired degranulation and reduced cytotoxicity. Bulk RNA sequencing showed that VKO NK cells upregulated activation, cytokine, DNA damage-response, type I interferon, NF-κB, and inflammasome-associated programs, while repressing ER-to-Golgi/degranulation pathways, glycolysis, fatty acid metabolism, oxidative phosphorylation, and mitochondrial quality-control genes. Functionally, VKO NK cells showed reduced mitochondrial mass, increased mitochondrial reactive oxygen species, and altered membrane potential. In the tumor model, VKO mice exhibited reduced NK cell infiltration and CXCR3 expression within tumors, and tumor-infiltrating NK cells displayed impaired cytotoxicity. NK cell depletion did not alter tumor control in VKO mice, despite enhancing tumor growth in wild-type mice. In humans, VISTA expression marked activated NK cell subsets with higher IFN-γ, CD69, and CD107a and reduced intracellular granzyme B/perforin. Thus, systemic VISTA deficiency uncouples NK cell activation from metabolic and cytolytic competence, whereas VISTA expression identifies activated human NK cell subsets.
PMID:43024833 | DOI:10.1093/jimmun/vkag282