Kojima Hidenobu, Morinelli Thomas A, Wang Yue, Chin Jackson L, Meyer Aaron S, Kao Yi-Chu, Kadono Kentaro, Yao Siyuan, Torgerson Taylor, Dery Kenneth J, Bhat Adil, Reed Elaine F, Kaldas Fady M, van der Windt Dirk J, Farmer Douglas G, Kupiec-Weglinski Jerzy W, Zhai Yuan
The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.
Am J Transplant. 2025 May;25(5):969-984. doi: 10.1016/j.ajt.2024.11.035. Epub 2024 Dec 28.
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 knockout (KO) recipients, in association with downregulation of group 1 ILCs genes, including interferon gamma. Antibody-mediated ILC depletion or interferon gamma neutralization in Rag2 KO recipients increased, while interferon gamma 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 interferon gamma during cold preservation decreased IRI. Thus, both recipient and donor group 1 ILCs protect liver grafts from IRI. Low-dose interferon gamma 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 interferon gamma. The c-FLIP levels were positively correlated with interferon gamma in pretransplant 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 interferon gamma-mediated cytoprotective role of group 1 ILCs in LT.
作为重要的免疫调节细胞，先天性淋巴细胞（ILCs）是否参与肝移植（LT）尚不清楚。在小鼠原位肝移植模型中，我们剖析了ILCs在肝缺血再灌注损伤（IRI）中的作用。野生型（WT）移植物在Rag2-γc双敲除（DKO）受体中比Rag2敲除（KO）受体遭受的IRI明显更高，这与包括干扰素γ在内的1型ILCs基因的下调有关。在Rag2 KO受体中，抗体介导的ILC耗竭或干扰素γ中和会增加肝移植损伤，而在DKO受体中进行干扰素γ治疗则会减少肝移植损伤。在供体方面，来自DKO小鼠或抗NK1.1处理的WT小鼠的移植物遭受的IRI明显更高，而在冷保存期间用干扰素γ处理的移植物则会降低IRI。因此，受体和供体的1型ILCs均能保护肝移植物免受IRI。低剂量干扰素γ在体外和体内上调了c-FLIP的表达，并保护肝细胞免受炎性细胞死亡。在人类肝移植活检中，单细胞RNA测序分析显示1型ILCs产生干扰素γ。在移植前活检中，c-FLIP水平与干扰素γ呈正相关。c-FLIP较高的移植物与较低的半胱天冬酶-8激活、IRI分级以及肝移植后早期移植物功能障碍的发生率相关。我们的研究揭示了1型ILCs在肝移植中一种新的干扰素γ介导的细胞保护作用。
