(Background) The immunosuppressive regimen currently used after organ transplantation reduces adaptive components. Therefore, the innate immune cells play pivotal roles in immune surveillance and defense against tumor and virus-infected cells after transplantation. Although the mTOR inhibitor (mTORi) is known as an immunosuppressive drug as well as a molecular targeting anti-cancer drug, its effects on innate immune cells is unclear. The liver is enriched with NK cells, important lymphocytes of the innate immune system, among which two distinct NK cell subsets have recently been identified: conventional DX5⁺TRAIL (TNF-related apoptosis-inducing ligand)^– NK cells and liver-resident DX5^–TRAIL⁺ NK cells. In this study, we analyzed the influence of mTORi on those NK cell subpopulations in mice.(Method) C57/BL6 mice were treated by intraperitoneal injection of mTORi (0-0.25mg/kg) for 7 days. Twenty four hours after last injection, liver mononuclear cells (LMNCs), splenocytes and pheripharal blood (PB) mononuclear cells were collected. The proportion of NK cells and various functional molecules on NK cells were analyzed by flow cytometry. (Result) The percentage of TCR^–NK1.1⁺NK fraction in LMNCs did not differ in both mTORi-treated and -untreated groups (11±0.35% vs 11.3±1.6%, respectively). Other lymphocyte fraction were not affected by mTORi treatment, either. mTORi significantly upregulated the expression of TRAIL on liver resident NK cells (25.6±1 vs 18.5±4.76, p value=0.03). Expression of NKp46 and CD69 was also higher on liver resident NK cells from the mTORi-treated group than that from the untreated group (NKp46: 117.65±3.7 vs 96.16±3.45, CD69: 54.1±6.04 vs 46.8±12.15, respectively). Those molecular enhancing activities were most strongly shown in 0.25mg/kg of mTORi and decreased dose dependency. Spleen NK cells and PB-NK cells showed no effect by mTORi-treatment.(Conclusion) The mTOR inhibitor has ability to enhance the liver NK cell activity. This result suggested that mTOR inhibitor is might be useful to maintain anti-microbe and anti-tumor immunity after transplantation.

CITATION INFORMATION: Saparbay J, Tanaka Y, Yano T, Ohdan H. The Beneficial Effects of mTOR Inhibitors on Liver Resident Natural Killer Cells. Am J Transplant. 2017;17 (suppl 3).

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