Ly6C+Sca-1+ virtual memory CD8+ T cells responding to IL-15/Ra complex promote chronic liver inflammation
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/Ra 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. Overall design: Comparison of gene expression patterns of wild-type (WT) naïve T cells, WT VM T cell, IL-15C-induced naïve T cells, IL-15C-induced VM T cells by mRNA sequencing analysis