Ligation of CD8alpha on human natural killer cells prevents activation-induced apoptosis and enhances cytolytic activity

Immunology. 2005 Nov;116(3):354-61. doi: 10.1111/j.1365-2567.2005.02235.x.


It has been previously shown that the subset of human natural killer (NK) cells which express CD8 in a homodimeric alpha/alpha form are more cytotoxic than their CD8- counterparts but the mechanisms behind this differential cytolytic activity remained unknown. Target cell lysis by CD8- NK cells is associated with high levels of effector cell apoptosis, which is in contrast to the significantly lower levels found in the CD8alpha+ cells after lysis of the same targets. We report that cross-linking of the CD8alpha chains on NK cells induces rapid rises in intracellular Ca2+ and increased expression of CD69 at the cell surface by initiating the influx of extracellular Ca2+ ions. We demonstrate that secretion of cytolytic enzymes initiates NK-cell apoptosis from which CD8alpha+ NK cells are protected by an influx of exogenous calcium following ligation of CD8 on the NK-cell surface. This ligation is through interaction with fellow NK cells in the cell conjugate and can occur when the target cells lack major histocompatibility complex (MHC) Class I expression. Protection from apoptosis is blocked by preincubation of the NK cells with anti-MHC Class I antibody. Thus, in contrast to the CD8- subset, CD8alpha+ NK cells are capable of sequential lysis of multiple target cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / immunology*
  • CD8 Antigens / blood
  • CD8 Antigens / immunology*
  • Cell Adhesion Molecules / blood
  • Cytotoxicity, Immunologic / immunology*
  • Granzymes
  • HLA Antigens / immunology
  • Humans
  • Immunophenotyping
  • Killer Cells, Natural / immunology*
  • Membrane Glycoproteins / blood
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Receptors, Immunologic / blood
  • Receptors, Immunologic / immunology
  • Receptors, KIR
  • Serine Endopeptidases / blood
  • Signal Transduction / immunology
  • Tumor Cells, Cultured


  • CD8 Antigens
  • CD8 antigen, alpha chain
  • Cell Adhesion Molecules
  • HLA Antigens
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Receptors, Immunologic
  • Receptors, KIR
  • Perforin
  • Granzymes
  • Serine Endopeptidases
  • GZMA protein, human