We have documented crucial role of TIM-3 dependent T cell dysfunction in mouse orthotopic liver transplantation (OLT). CEACAM1 (CM1; Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1), a recently identified TIM-3 ligand, may be essential for T cell priming/negative immune regulation. Although graft autophagy is important for hepatoprotection, whether CM1 regulates autophagy has not been defined. We aimed to determine the impact of donor liver CM1 signaling on host T cell regulation and stress resistance in mouse and human OLT. Groups of wild-type (WT) and CM1-deficient (CM1-KO) livers with extended (18h) cold storage were transplanted orthotopically to WT recipients (C57/BL6→C57/BL6), followed by sample collection at 6h post-OLT (n=5/gr). Disruption of CM1 signaling at the graft site depressed LC3B expression, and exacerbated hepatocellular damage, evidenced by sALT/AST levels, Suzuki's histological grading and frequency of TUNEL+ cells (p<0.05). FACS-assisted PBL analysis in CM1-KO→WT hosts showed depressed staining for TIM3 and PD1 but increased for Tbet in T cells, as compared to WT→WT group. CM1-KO liver grafts had increased levels of IL2, IL1β, TNFα, CXCL1, CXCL2, and enhanced Ly6G+ and CD11b+ cell infiltration (p<0.05). Consistent with in vivo findings, CM1-deficient hepatocyte cultures were more susceptible to H2O2-induced cell death, evidenced by increased cleaved caspase 8/3, frequency of TUNEL+ cells and elevated LDH activity (p<0.05) in vitro. To assess putative clinical relevance of graft CM1 cytoprotection, sixty human hepatic biopsies from OLT recipients were collected under IRB protocol at 2h post-reperfusion. CM1 expression was analyzed by Western blots and patients were classified into low-CM1 (n=30) and high-CM1 (n=30) groups. Indeed, the low-CM1 group had decreased LC3B expression (p<0.05), suppressed LC3B-II/I ratio (p<0.05), higher sALT levels at POD1 (p<0.05), and higher frequency of early allograft dysfunction (p<0.05). Conclusion: This translational study identified the essential organ protective function of hepatocellular CM1 in OLT not only by priming TIM-3 dependent T cell inactivation, possible via immune exhaustion, but also by promoting hepatic autophagy and stress resistance.

CITATION INFORMATION: Nakamura K., Kageyama S., Kujawski M., Ito T., Aziz A., Oncel D., Ke B., Sossa R., Reed E., Kaldas F., Busuttil R., Kupiec-Weglinski J. Graft CEACAM1 is Essential to Autophagy Induction and T-Cell Regulation in Liver Transplantation: From Mouse-to-Human Am J Transplant. 2017;17 (suppl 3).

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