*Purpose: Although NKp46⁺group 3innate lymphoid cells (ILCs) (RORγt⁺IL-22-producing NKp46⁺cells) were reported to protect liver against ischemia-reperfusion injury (IRI), no study has demonstrated the contribution of ILCs in liver transplantation. Therefore, we investigate whether and how ILCs affect liver transplant outcomes in a mouse orthotopic liver transplantation (OLT) model.

*Methods: Wild type (WT) C57BL/6J mouse liver grafts were subjected to the extended cold storage (4°C/18 hours) in UW solution to mimic the marginal donor livers in human OLT.To evaluate the role of ILCs in OLT, we transplanted the cold-stored grafts into: WTmice, Rag2 knockout (KO) mice that lack T and B cells, and Rag2-common-γ-chain double KO (Rag2-γc-DKO) mice that lack ILCs in addition to T and B cells (all in C57BL/6J background). We used 0.5 mg of anti-CD90.2 antibody (Bio X Cell) intravenously at 48 hours prior to transplantation to deplete ILCs in Rag2 KO mice. Liver IRI was evaluated at 6 hours post-Tx.

*Results: Compared with WT and Rag2 KO, but not Rag2-γc-DKO, recipients were protected from liver IRI, as documented by serum ALT and AST levels, Suzuki’s histological grading, quantities of infiltrating CD11b+ macrophages/Ly6G+ neutrophils, and frequency of TUNEL+ cells. Furthermore, depletion of ILCs with CD90.2 increased hepatocellular injury in Rag2 KO mice and diminished Rag2 KO and Rag2-γc-DKOmouse disparities, suggesting that recipient derived ILCs might exert protective function against IRI in OLT. The intra-graft gene expression of T-box transcriptional factor T-bet significantly increased while IL-23 decreased in Rag2 KO recipients as compared with Rag2-γc-DKOcounterparts.

*Conclusions: This study is the first to reveal that ILCs might protect OLT from IRI, which provides us a novel therapeutic target for future clinical application in transplant recipients.

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