Enclysis is the enclosure and lysis of regulatory T cells by hepatocytes: our first paper on this new process was released in November 2019 (Davies et al., Cell Reports 2019). We are exploring ways to use this pathway for the benefit of patients with liver diseases and liver cancer. Read on to learn how enclysis fits with our current understanding of liver immune regulation.
The video below shows a hepatocyte cancer cell (green cell membrane, red cell cytoplasm) engulf a live T cell (blue). The T cell (shown by the white arrow) remains inside the hepatocyte, connected to the endocytic pathway. Also notice the bright red dead cell debris that the hepatocyte engulfed by phagocytosis.
Our livers are constantly filtering blood from the gut, rich in foreign proteins from food and microbial products. To avoid triggering immune responses against these harmless chemicals, the liver has evolved natural mechanisms to dampen inflammation.
Regulatory T cells (Treg cells) function by reducing proliferation of effector immune cells and they are enriched in the liver. So how can the liver defend itself against infection in the presence of high Treg cell numbers?
We propose that when immune cells are needed to control infection, hepatocytes eliminate Treg cells by enclysis. When infection is resolved, Treg numbers are restored in a manner controlled by endothelial barriers.
80% of the liver volume comprises of hepatocytes, epithelial cells that in health are shielded from immune cells by sinusoidal endothelial layers. Hepatocytes are excellent phagocytes and rapidly clear dead cells to prevent inflammation (See figure below and Davies et al., Frontiers in Immunology 2018).
During inflammation, endothelial cells become activated and allow passage of Treg cells to hepatocyte regions, where they are eliminated by enclysis. When infection is resolved, the endothelial barrier is restored and Treg cell numbers rise again to balance immunity and prevent liver damage.
We are investigating ways to manipulate enclysis to spare the livers of patients with chronic inflammation and to boost anti-cancer immunity in those with liver cancer.