The Role And The Mechanism Of Autophagy In The Anti-tumor Effect Of NK Cells

Macroautophagy (hereafter referred to autophagy) is an evolutionary conserved metabolic mechanism in eukaryocytes which depends on two ubiquitin-like protein conjugation systems, Atg5-Atg12-Atg16L for initiation and Atg8/LC3for elongation. After being enwrapped by autophagosome, cytosolic components would be delivered to lysosome for degradation.NK cell, as an important part of innate immune system, plays a key role in cytolysis and eradicating microbe invaded host cells. Till now, there are no reports about the relationship between autophagy and NK cell cytotoxicity. Here, we utilized Atg3and Atg7conditional knock-out mice to explore the role of autophagy in orchestrating NK cell cytotoxicity function.In the present study, we used tamoxifen to knock down the autophagy-related gene Atg3in Atg3f/f ER-cre mice and Atg7in Atg7f/f UbiER-cre mice. We found that the NK cells from autophagy-deficient mice showed higher expression level of perforin and granzymB compared with NK cells from control mice, and therefore possessed increased cytotoxicity activity in vitro. We also found that autophagy deficient mice exhibited more obvious anti-tumor effect on the NK-senstive RAM-S tumor in vivo. Furthermore, autophagy deficiency had no effect on the maturation and the IFN-y production of NK cells. The inhibitory receptors and the activating receptors in surface of NK cell did not changed after Atg7gene knockdwon. The release of cytolytic granules detected by CD107a staining was not impaired in NK cells from Atg7knockout mice compared with those from control mice. These data indicated that the increased expression of perforin and granzymB in autophagy-deficient NK cells resulted in the higher cytotoxicity activity, and the underlying mechanism need further explored.