KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation

EMBO J. 2015 Oct 1;34(19):2441-64. doi: 10.15252/embj.201489838. Epub 2015 Aug 17.

Abstract

Phagocytosis of apoptotic cells by both professional and semi-professional phagocytes is required for resolution of organ damage and maintenance of immune tolerance. KIM-1/TIM-1 is a phosphatidylserine receptor that is expressed on epithelial cells and can transform the cells into phagocytes. Here, we demonstrate that KIM-1 phosphorylation and association with p85 results in encapsulation of phagosomes by lipidated LC3 in multi-membrane organelles. KIM-1-mediated phagocytosis is not associated with increased ROS production, and NOX inhibition does not block LC3 lipidation. Autophagy gene expression is required for efficient clearance of apoptotic cells and phagosome maturation. KIM-1-mediated phagocytosis leads to pro-tolerogenic antigen presentation, which suppresses CD4 T-cell proliferation and increases the percentage of regulatory T cells in an autophagy gene-dependent manner. Taken together, these data reveal a novel mechanism of epithelial biology linking phagocytosis, autophagy and antigen presentation to regulation of the inflammatory response.

Keywords: MHC; T regs; acute kidney injury; biomarker; heterophagy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigen Presentation / physiology*
  • Apoptosis
  • Autophagy-Related Protein 5
  • Autophagy-Related Protein-1 Homolog
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Proliferation / physiology
  • HEK293 Cells
  • Hepatitis A Virus Cellular Receptor 1
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / immunology*
  • Lipoylation / physiology
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / immunology*
  • Phagocytosis / physiology*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology*
  • Reactive Oxygen Species / immunology
  • Receptors, Virus / genetics
  • Receptors, Virus / immunology*

Substances

  • ATG5 protein, human
  • Autophagy-Related Protein 5
  • HAVCR1 protein, human
  • Hepatitis A Virus Cellular Receptor 1
  • Intracellular Signaling Peptides and Proteins
  • MAP1LC3A protein, human
  • Membrane Glycoproteins
  • Microtubule-Associated Proteins
  • Reactive Oxygen Species
  • Receptors, Virus
  • Autophagy-Related Protein-1 Homolog
  • Protein Serine-Threonine Kinases
  • ULK1 protein, human