Degranulation plays an essential part in regulating cell surface expression of Fas ligand in T cells and natural killer cells

Nat Med. 1999 Jan;5(1):90-6. doi: 10.1038/4779.

Abstract

Fas ligand (FasL) triggers apoptosis during cytotoxicity mediated by cytotoxic T lymphocytes and during immune downregulation. The ability of T cells and natural killer cells to trigger apoptosis through this mechanism is controlled by the cell surface expression of FasL (ref. 2). Because FasL expression is up-regulated on activation, FasL was thought to be delivered directly to the cell surface. Here we show that newly synthesized FasL is stored in specialized secretory lysosomes in both CD4+ and CD8+ T cells and natural killer cells, and that polarized degranulation controls the delivery of FasL to the cell surface. In this way, FasL-mediated apoptosis is finely controlled by receptor-mediated target-cell recognition. The cytoplasmic tail of FasL contains signals that sort FasL to secretory lysosomes in hemopoietic cells. This pathway may provide a general mechanism for controlling the cell surface appearance of proteins involved in immune regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / analysis
  • Antigens, Differentiation, T-Lymphocyte / analysis
  • CD4-Positive T-Lymphocytes / chemistry
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / chemistry
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cathepsin D / analysis
  • Cell Degranulation*
  • Cell Fractionation
  • Cell Line
  • Fas Ligand Protein
  • Gene Expression
  • Granzymes
  • HeLa Cells
  • Humans
  • Killer Cells, Natural / chemistry
  • Killer Cells, Natural / metabolism*
  • Lectins, C-Type
  • Lysosomes / metabolism
  • Membrane Glycoproteins / analysis
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Perforin
  • Platelet Membrane Glycoproteins / analysis
  • Pore Forming Cytotoxic Proteins
  • Rats
  • Serine Endopeptidases / analysis
  • Tetraspanin 30

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD63 protein, human
  • CD69 antigen
  • Cd63 protein, mouse
  • Cd63 protein, rat
  • FASLG protein, human
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Lectins, C-Type
  • Membrane Glycoproteins
  • Platelet Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Tetraspanin 30
  • Tnfsf6 protein, rat
  • Perforin
  • Granzymes
  • Serine Endopeptidases
  • GZMA protein, human
  • Cathepsin D