*Purpose: Innate lymphoid cells (ILCs), a heterogeneous population of non-B non-T lymphocytes, have been found in recent years to plays key regulatory roles in tissue inflammatory response against infectious and non-infectious agents. The question of whether they are involved in the pathophysiology of liver ischemia-reperfusion injury (IRI), particularly in the setting of orthotopic liver transplantation (OLT), is largely unknown.

*Methods: Mouse liver grafts were subjected to the extended cold storage (4°C/18 hours) to mimic the marginal donor livers in human OLT. To evaluate the role of recipient ILCs in OLT, we transplanted the cold-stored WT B6 grafts into: WT, or Rag2 knockout (KO, lack T and B cells), or Rag2-common-γ-chain double KO (Rag2-γc DKO, lack ILCs/NK and T and B cells) recipient mice (all in B6 background). Liver IRI was evaluated at 6h post Tx. Additionally, we treated Rag2 KO recipient mice with anti-CD90.2 (0.5 mg at 72h and 0.25 mg at 24h prior to OLT, intraperitoneal injection), or anti-NK1.1 (0.25 mg at 48h prior to OLT, intravenous injection; i.v.), or anti-interferon-γ (IFN-γ) antibodies (0.5mg immediately after reperfusion, i.v.) to deplete all ILCs, or type 1 ILCs (ILC1s), or to neutralize IFN-γ, respectively.

*Results: Compared with WT controls, Rag2 KO recipients were protected from liver IRI; Rag2-γc DKO recipients, however, developed significantly higher levels of liver IRI, as documented by levels of serum ALT/AST and Suzuki’s histological grading. Depletion of total ILCs with anti-CD90.2 increased liver injuries in Rag2 KO mice and diminished the differences between Rag2 KO and Rag2-γc DKO recipients. Quantitative RT-PCR analysis of intrahepatic gene transcripts revealed no differences in the signature gene expression profiles of ILC2, ILC3, ILCreg, but ILC1. Levels of T-box transcriptional factor (T-bet) and IFN-γ were significantly higher in OLTs of Rag2 KO recipients as compared with those of Rag2-γc DKO and Rag2 KO treated with anti-CD90.2 Abs. In addition, depletion of ILC1s by anti-NK1.1 Abs and neutralization of IFN-γ exacerbated IRI of OLTs in Rag2 KO recipients.

*Conclusions: Recipient’s ILCs, in particular ILC1s/NK cells protect OLTs from IRI via IFN-γ. This study demonstrates, for the first time, unique roles of ILC1s in liver IRI, and provides us a novel therapeutic target for future clinical application in transplant recipients.

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