Hepatocytes Delete Regulatory T Cells by Enclysis, a CD4 + T Cell Engulfment Process

Cell Rep. 2019 Nov 5;29(6):1610-1620.e4. doi: 10.1016/j.celrep.2019.09.068.

Abstract

CD4+ T cells play critical roles in directing immunity, both as T helper and as regulatory T (Treg) cells. Here, we demonstrate that hepatocytes 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. Enclysis is selective for CD4+ but not CD8+ cells, independent of antigen-specific activation, and occurs in human hepatocytes in vitro, ex vivo, and in vivo. Intercellular adhesion molecule 1 (ICAM-1) facilitates T cell early adhesion and internalization, whereas hepatocytes form membrane lamellipodia or blebs to mediate engulfment. T cell internalization is unaffected by wortmannin and Rho kinase inhibition. Hepatocytes engulf Treg cells more efficiently than non-Treg cells, but Treg cell-containing vesicles preferentially acidify overnight. Thus, enclysis is a biological process with potential effects on immunomodulation and opens a new field for research to fully understand CD4+ T cell dynamics in liver inflammation.

Keywords: T cells; cell-in-cell structures; efferocytosis; emperipolesis; enclysis; endocytosis; entosis; hepatocytes; liver; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / ultrastructure
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Adhesion / genetics
  • Cell Line
  • Endocytosis / genetics
  • Endocytosis / immunology*
  • Endosomes / genetics
  • Endosomes / immunology*
  • Forkhead Transcription Factors / metabolism
  • Hepatocytes / metabolism*
  • Humans
  • Immune Tolerance
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Liver / immunology
  • Lysosome-Associated Membrane Glycoproteins / metabolism
  • Lysosomes / metabolism
  • Microscopy, Electron, Scanning
  • Pinocytosis
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / ultrastructure
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • ICAM1 protein, human
  • LAMP1 protein, human
  • Lysosome-Associated Membrane Glycoproteins
  • beta Catenin
  • Intercellular Adhesion Molecule-1