Autophagy Negatively Regulates The Activation And Function Of Cd8~+T Cells

Autophagy is a major catabolic process in which intracellular membrane structures include protein complexes and organelle,then fuse with lysosomes to form lysoautophagosomes,and finally result in degradation of cytoplasmic components.Autophagy is a physiological process to maintain cellular homeostasis,and thus alterations of autophagy activity may change the catabolic process of its substrates.CD8+ T cell,as an important part of adaptive immune system,plays an key role in eliminating the virus-infected cells and tumor cells.However,the role of autophagy in the activation and cytotoxicity in CD8+T cells still remain unknown.Here,we utilized autophagy-related gene conditional knock-out mice to determine how autophagy regulates the activation and function of CD8+ T cell.We found that the PBMCs isolated from patients with Crohn's disease exhibited lower autophagic activity and higher cytotoxicity,showing negative correlation.The previous data from our lab also showed that Atg3-deficient CD8+ T cells exhibited stronger cytotoxicity compared with wild type CD8+T cells.To exclude Atg3 specific effect,here we observed the function of Atg7-deficient CD8+ T cells,which showed high cytolytic activity both in vitro and in vivo.Therefore,autophagy-deficient CTL possess stronger anti-tumor effect in vivo,and prolonged the survival of tumor-bearing mice.We further found that autophagy-deficient CD8+ T cells is susceptible to be activated,evidence as higher level of activation markers and proliferation activity.Mechanism analysis revealed the phosphorylation of ZAP-70,PLCyl and ERK,intracellular calcium flux,the nuclear translation of T-bet all be enhanced in autophagy-deficient CD8+ T cells.The expression level of TCR? on the surface of autophagy-deficient CD8+ cells also increased.Further study is needed for elucidate the exact role of autophagy in CD8+ T cells.