Memory-like Liver Natural Killer Cells are Responsible for Islet Destruction in Secondary Islet Transplantation

We previously demonstrated the pivotal role of natural killer (NK) cells in islet graft loss during the early phase after intraportal syngeneic islet transplantation (IT). Liver-resident DX5^- NK cells were reported to possess memory-like properties, distinguishing them from conventional DX5⁺ NK cells. Here, we investigated the impact of primary IT-induced liver DX5^- NK cells on the engraftment of secondary-transplanted islets in mice. The culture of liver NK cells isolated from naive mice with TNF-α, IFN-γ, and IL-lβ, mimicking instant blood-mediated inflammatory reaction, led to significantly increased DX5^- NK cell percentage among total liver NK cells. Consistently, the prolonged expansion of DX5^- CD69⁺ TRAIL⁺ CXCR3⁺ NK cells was observed after intraportal IT of 300 syngeneic islets (marginal mass). In most diabetic mice, 400 syngeneic islets of primary IT were sufficient to achieve normoglycaemia, whereas the same mass after secondary IT failed to induce normoglycaemia in mice that received 200 syngeneic islets during primary IT. These findings indicated that liver-resident DX5^- NK cells significantly expanded even after syngeneic IT, and that these memory-like NK cells may target both originally engrafted and secondary-transplanted islets. Furthermore, anti-TNF-α treatment suppressed the expansion of liver-resident DX5^- NK cells, resulting in successful islet engraftment after sequential ITs.