Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D

Nat Immunol. 2002 Dec;3(12):1142-9. doi: 10.1038/ni858. Epub 2002 Nov 11.


Optimal lymphocyte activation requires the simultaneous engagement of stimulatory and costimulatory receptors. Stimulatory immunoreceptors are usually composed of a ligand-binding transmembrane protein and noncovalently associated signal-transducing subunits. Here, we report that alternative splicing leads to two distinct NKG2D polypeptides that associate differentially with the DAP10 and KARAP (also known as DAP12) signaling subunits. We found that differential expression of these isoforms and of signaling proteins determined whether NKG2D functioned as a costimulatory receptor in the adaptive immune system (CD8+ T cells) or as both a primary recognition structure and a costimulatory receptor in the innate immune system (natural killer cells and macrophages). This strategy suggests a rationale for the multisubunit structure of stimulatory immunoreceptors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Humans
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • NK Cell Lectin-Like Receptor Subfamily K
  • Protein Subunits / genetics
  • Protein Subunits / immunology
  • RNA Splicing / immunology*
  • Receptors, Immunologic / genetics*
  • Receptors, Immunologic / immunology*
  • Receptors, Natural Killer Cell
  • Signal Transduction / genetics
  • Signal Transduction / immunology


  • Adaptor Proteins, Signal Transducing
  • HCST protein, human
  • Hcst protein, mouse
  • KLRK1 protein, human
  • Klrk1 protein, mouse
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Protein Subunits
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • TYROBP protein, human

Associated data

  • GENBANK/AF030313
  • GENBANK/AF054819