Understanding immune cell interactions with liver cells is critical to design effective therapies for chronic liver diseases, which can lead to fibrosis, cirrhosis, and end-stage liver diseases requiring a transplant.
A new study, published in Cell Reports, has uncovered the phenomenon of enclysis – where liver cells engulf and devour CD4+ T cells – opening up a new field of study to investigate the role of T cell dynamics in liver inflammation.
Dr Zania Stamataki, Senior Lecturer in Liver Immunology, explains how her lab came to discover the liver’s taste for T cells:
CD4+ T cells play critical roles in directing immunity, both as T helper and as regulatory T (Treg) cells.
Our study has demonstrated that hepatocytes - liver cells - can modulate T cell populations through engulfment of live CD4+ lymphocytes.
We term this phenomenon enclysis to reflect the specific enclosure of CD4+ T cells in hepatocytes.
This work started as a side project, delivered in a long and winding road of experiments funded by small grants like the Wellcome Trust Institutional Support Fund that allowed us to pursue this weird phenomenon for CD4+ T cells that we noted when studying virus transmission.
Thanks to the flexibility of the Royal Society Dorothy Hodgkin fellowship, and with the help of our brave PhD student Scott Davies (funded by the MRC), we now understand that hepatocytes have a taste for regulatory T cells, which dampen inflammation.
Scott spent his PhD showing that enclysis is a process distinct to the clearance of apoptotic cells (efferocytosis), and with the help of Joe Grove at UCL’s Institute of Immunity and Transplantation, we noticed different membrane alterations during cell capture by scanning electron microscopy.
Enclysis was distinct to all the known ‘E’s for cell-in-cell structures: efferocytosis, entosis, and emperipolesis, as shown in this figure:
A collaboration with Professor Yuehua Huang showed faith in this project, and the talented clinician scientist Emily Li helped us demonstrate that regulatory T cells specifically end up in acidic compartments within the hepatocytes. Sorry Tregs!
In liver autoimmunity, we found higher incidence of regulatory T cells inside hepatocytes. Unlike previously described cell-in-cell mechanisms, enclysis involves membrane bleb formation and shares features with macropinocytosis – providing a further aspect of immune regulation in the liver which could be exploited in drug discovery. So, we’re now working to target enclysis for patient benefit, with the help of high content imaging enthusiast Alex Wilkinson, as well as Professor David Wraith and Professor David Hodson.