IL15 — Driven Crosstalk Between Liver Sinusoidal Endothelial Cells and CD8⁺ Tissue-Resident Memory T Cells Promotes Inflammation in Alcohol-Associated Hepatitis

Background: Alcohol-associated hepatitis (AH) is a severe inflammatory liver condition driven by dysregulated immune responses. CD8 T cells accumulate in the liver during AH, yet their functional role remains poorly defined. Approach & Results: Single-cell RNA sequencing (scRNA-seq) in a murine AH model revealed a distinct population of CD8 tissue-resident memory T cells (TRM) with heightened activation and proinflammatory cytokine production. Analysis of human AH liver scRNA-seq data, along with immunohistochemistry validation, supported CD8 TRM enrichment in diseased tissue. IL15 emerged as a prominent pathway linked to TRM activation, and IL15 blockade reduced TRM abundance and attenuated EtOH/LPS-induced liver injury. Mechanistically, liver sinusoidal endothelial cells (LSECs) not only provided a structural niche for TRM retention but also amplified IL15 signaling. In vitro, co-culture experiments demonstrated that LSECs intensified activation in pre-stimulated CD8 T cells in a stimulus-dependent manner: under IL15 stimulation, LSECs boosted effector function without inducing cell death, whereas under TCR-stimulation, LSECs drove hyperactivation and activation-induced cell death. Bulk RNA-seq and phospho-protein analysis identified the PI3K–AKT pathway as a shared pathway enhanced by LSEC co-culture in activated CD8 T cells. These findings define a context-dependent mechanism in which LSECs promote IL15-driven signaling through AKT pathway amplification, promoting TRM persistence and inflammatory activity in AH. Conclusion: IL‑15–associated signaling within the hepatic microenvironment, shaped by LSEC–CD8 T cell interactions, promotes activation and persistence of CD8 TRM cells in alcohol‑associated hepatitis. Targeting IL15–LSEC–AKT axis may disrupt pathogenic TRM niches and represents a promising therapeutic strategy for severe AH.