Negative regulation of natural killer cell function by EAT-2, a SAP-related adaptor

Nat Immunol. 2005 Oct;6(10):1002-10. doi: 10.1038/ni1242. Epub 2005 Aug 28.

Abstract

EAT-2 is an adaptor expressed in innate immune cells, including natural killer (NK) cells. It is closely related to the adaptor SAP, which regulates signaling lymphocyte activation molecule (SLAM)-related receptors by recruiting the kinase FynT to the receptors. Here we have studied the function of EAT-2 in NK cells by creating mice lacking or overexpressing EAT-2. Like SAP, EAT-2 was associated with the SLAM-related receptor 2B4 in NK cells. However, unlike SAP, EAT-2 was an inhibitor of NK cell function. EAT-2 repressed natural cytotoxicity and interferon-gamma secretion by a mechanism involving tyrosine phosphorylation of its C terminus. We have demonstrated a similar function for the adaptor ERT, a newly identified SAP family member expressed in mouse NK cells. These data identify a previously unknown mechanism of NK cell inhibition. Moreover, they indicate that EAT-2 and SAP have distinct and at times opposing functions in natural immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Antigens, CD / genetics
  • Antigens, CD / physiology
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Cytotoxicity, Immunologic
  • Down-Regulation
  • Interferon-gamma / metabolism
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Molecular Sequence Data
  • Phosphorylation
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / physiology
  • Sequence Alignment
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Signaling Lymphocytic Activation Molecule Family
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Tyrosine
  • src Homology Domains / genetics
  • src Homology Domains / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Cd244a protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Sh2d1a protein, mouse
  • Sh2d1b1 protein, mouse
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Signaling Lymphocytic Activation Molecule Family
  • Transcription Factors
  • Tyrosine
  • Interferon-gamma

Associated data

  • SWISSPROT/DQ140178