ApolipoproteinE+ Kupffer cells maintain immune homeostasis following liver transplantation by inducing CD8+ T cell exhaustion.

Kupffer cells (KCs) are key drivers of immune homeostasis following liver transplantation (LT). We identified a specialized APOE+ KC subset enriched in stable and tolerant grafts by integrating human single-cell RNA sequencing with murine orthotopic LT models. These APOE+ KCs function as a central signaling hub, communicating with CD8+ tissue-resident memory (TRM) T cells via the CXCL16-CXCR6 axis. Using APOE-knockout models, we demonstrated that donor-derived APOE was essential for KC suppressive capacity. APOE deficiency exacerbates acute rejection by preventing CD8+ TRM cells from upregulating inhibitory checkpoints (PD-1 and TIGIT) and from transitioning into an exhausted state, which is necessary to resolve alloreactivity. Clinically, elevated donor serum APOE inversely correlates with recipient model for end-stage liver disease (MELD) scores and liver injury. Ultimately, APOE+ KCs promote graft tolerance by driving CD8+ TRM exhaustion, establishing donor APOE as a critical prognostic biomarker and dual therapeutic target for optimizing transplant survival.