Group 1 innate lymphoid cells protect liver transplants from ischemia-reperfusion injury via an interferon-γ-mediated pathway

As important immune regulatory cells, whether innate lymphoid cells (ILCs) are involved in liver transplantation (LT) remains unclear. In a murine orthotopic LT model, we dissected roles of ILCs in liver ischemia-reperfusion injury (IRI). Wild type (WT) grafts suffered significantly higher IRI in Rag2-γc double knockout (DKO) than Rag2 KO recipients, in association with downregulation of group 1 ILCs genes, including IFN-γ. Antibody-mediated ILC depletion or IFN-γ neutralization in Rag2 KO recipients increased, while IFN-γ treatment in DKO recipients reduced, liver graft injuries. At the donor side, grafts from DKO mice or anti-NK1.1-treated WT mice suffered significantly higher IRI, while grafts treated with IFN-γ during cold preservation decreased IRI. Thus, both recipient and donor group 1 ILCs protect liver grafts from IRI. Low-dose IFN-γ upregulated c-FLIP expression in vitro and in vivo, and protected hepatocytes from inflammatory cell death. In human liver graft biopsies, single-cell RNA-sequencing analysis revealed group 1 ILCs produce IFN-γ. The c-FLIP levels were positively correlated with IFN-γ in pre-transplant biopsies. Grafts with higher c-FLIP were associated with lower caspase-8 activation, IRI gradings, and frequency of early allograft dysfunction post-LT. Our study reveals a novel IFN-γ-mediated cytoprotective role of group 1 ILCs in LT.