Immune suppressive drugs negatively regulate the CD8+ T cells function by acetyltransferase p300 induced canonical and non-canonical autophagy

Abstract

Abstract Macroautophagy is the mainly regulated form of autophagy that maintains the cellular homeostasis and degraded the transported cargoes. It is initiated by the protein kinase complex which initiation by receiving two signals pathway mTORC1-AMPK-ULK1 and ULK1-PI3K-PI3P. Currently, autolysosomes accumulate during in vitro CD8+ T cells aging and may participate in inducing death sensitization of senescent cells. Aplastic Anemia is a hyperimmune disease and mainly mechanism of AA is the T cells subsets imbalance such as CD8+ T cells abnormal activation and hyperfunction. Therefore, we focused on the role of autophagy in the CD8+ T cells and supposed whether some immunosuppress drugs induced the cells autophagic death to therapy the hyperimmune diseases. We found that the acetyltransferase p300 obviously increases in the AA patients and is related with the severity of illness. Previous studies have reported that canonical autophagy is regulated by the mTORC1-p300 axis. p300, which acetylation occurs on its substrates, is a critical bridge in the p300-VPS34 axis mediated non-canonical autophagy. We showed that there is autophagy deficiency and acetylation deficiency in the CD8+ T cells. We first researched the canonical autophagy in the CD8+ T cells, notably, the expression of p300 also decreased after the immunosuppressive drugs therapy. Our findings provide a framework for understanding how immunosuppressive drugs effect on the AA autophagy deficiency mechanism and we proved that CD8+ T cells was negatively regulated by immunosuppressive drugs by p300-mediated canonical autophagy pathway and non-canonical autophagy pathway.