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Ly6C+Sca-1+ virtual memory CD8+ T cells responding to IL-15/Rα complex promote chronic liver inflammation

ABSTRACT: Virtual memory (VM) CD8+ T cells are cytokine-driven, memory-phenotype lymphocytes maintained independently of antigen exposure. However, their role in chronic hepatic inflammation remains poorly defined. Here, we examined whether signaling through the IL-15/Rα complex (IL-15C) modulates VM CD8+ T cell responses during chronic liver injury. Mice were pretreated with IL-15C prior to induction of chronic liver injury using thioacetamide (TAA). VM CD8+ phenotypes, transcriptional profiles, and hepatic accumulation were analyzed by flow cytometry and mRNA sequencing. Type I interferon-deficient and CD8-depleted mouse model were used to assess the contribution of cytokine signaling and CD8+ T cells to the observed responses. IL-15C induced robust expansion of VM CD8+ T cells in both the spleen and liver, with preferential enrichment of a Ly6C+Sca-1+ subsets. IL-15C reprogrammed VM CD8+ T cells toward an effector and migratory phenotype, characterized by increased expression of EOMES, T-bet, NKG2D, and inflammatory chemokine receptors, along with reduced tissue-residency signatures. During chronic TAA-induced liver inflammation, VM CD8+ T cells, particularly the Ly6C+Sca-1+ subsets, accumulated in the liver, and IL-15C pretreatment further enhanced hepatic immune cell infiltration and was associated with sustained liver injury and fibrotic responses. Notably, IL-15-induced VM T cells exhibited reduced PD-1 expression and sustained NKG2D expression, especially within CD62L+ and CD69+ VM T cell populations. These findings demonstrate that IL-15C drives the expansion and phenotypic reprogramming of VM CD8+ T cells toward an effector-like, migratory state and is associated with enhanced hepatic immune cell infiltration during chronic liver injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE316113 | GEO | 2026/02/01

REPOSITORIES: GEO

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Project description:Gene-expression profiles of hepatic stellate cells isolated from IL15R-alpha knockout mouse IL-15 and its high affinity receptor IL-15Rα are widely expressed in immune cells including dendritic cells and macrophages and non-immune cells such as hepatocytes, oval cells and hepatic stellate cells (HSC). IL-15 signaling has important functions in natural killers (NK), natural killers T (NKT) and cytotoxic T (CD8+T) cell homeostasis and also in liver regeneration. We hypothesized that IL-15 may have a protective role during liver fibrosis progression due to its role in NK cell homeostasis. We compared fibrosis progression in IL-15Rα knockout mice (IL-15RαKO) to wild type mice using two mechanistically distinct models, chronic carbon tetrachloride (CCl4) exposure and bile duct ligation (BDL). Enhanced fibrosis progression was observed in IL-15RαKO mice in both models. Furthermore, using congenic bone marrow transplantation (BMT), we demonstrated an unexpected role for IL-15 signaling in hepatic resident cells for the maintenance of liver NK and CD8+T cell populations. Using this approach, transplanting IL-15RKO hematopoietic cells results in NK defect that surprisingly is not reflected in a change of fibrosis progression. However, chimeric mice with defect of IL-15R on liver resident cells have similar NK defects and significant more fibrosis after CCL4 liver injury. This supports a direct protective, anti-fibrogenic role for IL-15R on one of the radioresistant liver cell populations (hepatocytes, HSC and sessile Kupffer cells). Microarray analysis of IL15RKO HSC suggests up-regulation of collagen transcripts and down-regulation of pathways involved in cell proliferation/survival. Finally, activated HSCs isolated from IL-15RKO mice show increased collagen secretion and as predicted, no changes in the growth curves. In summary, IL-15Rα signaling has an anti-fibrotic effect through both BM-derived and hepatic resident cells. These findings establish a rationale to explore IL-15 signaling in HSC as a potential therapeutic target in liver fibrogenesis.

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Ly6C+Sca-1+ virtual memory CD8+ T cells responding to IL-15/Rα complex promote chronic liver inflammation

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