*Purpose: 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 microbes and neoplastic 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. In this study, we analyzed the influence of mTORi on natural Killer (NK) cell subpopulations in mice.

*Methods: C57/BL6 mice were treated by intraperitoneal injection of mTORi in three different dose(0-0.25mg/kg) for 7 days. Twenty four hours after the last injection, liver mononuclear cells (LMNCs), splenocytes and peripheral blood (PB) mononuclear cells were collected. The proportion of NK cells and various functional molecules on NK cells were analyzed by flow cytometry. The cytotoxic activity of liver NK cells against hepatocellular carcinoma was analyzed by ⁵¹Cr release assay.

*Results: The proportion of TCR^–NK1.1⁺NK fraction in LMNCs did not differ in both mTORi-treated and -untreated groups (11.0±0.3% vs 11.3±1.6%, respectively). However, mTORi significantly upregulated the expression level of TRAIL on liver NK cells in dose dependency (26.2±2.0 in 0.0125 mg/kg dose group, 27.0±2.0 in 0.0250 mg/kg dose group, 25.6±1.0 in 0.25 mg/kg dose group vs 18.5±4.76 in untreated, p=0.05, p= 0.02, p =0.03 respectively). mTORi treatment increased slightly the immature NK 1.1⁺ TCR β ^– CD11b ^– CD 27^– TRAIL ⁺ cell subset in the liver, notably that TRAIL expression was increased on this distinct Liver NK cells only (MFI TRAIL was 373.3±2.3 in control group vs 587.2±15.6 in treated group), while TRAIL expression on other subsets were not affected .The proportion of NK cells, expression of their activation markers in the spleen were not affected by mTORi treatment. Liver NK cells from mTORi treated mice showed significantly higher cytotoxicity against TRAIL-sensitive Hepa1-6 cells (30.1% ± 13.0 vs 13.5 %± 6.0, p=0.009). Cytotoxicity against TRAIL resistant YAC-1 mouse lymphoma was also enhanced after mTORi treatment (53.6 % ± 4.4 vs 39.9% ± 1.2).

*Conclusions: mTOR inhibitor has ability to enhance liver resident NK cell activity . This result suggests that mTOR inhibitor might be useful to maintain anti-microbe and anti-tumor immunity even under immunosuppressive condition after transplantation.

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