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Killer cell inhibitory receptors: diversity, specificity, and function

E O Long1, D N Burshtyn, W P Clark

  • 1Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, MD 20852, USA. elong@nih.gov

Immunological Reviews
|February 1, 1997
PubMed
Summary
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Natural killer (NK) cells use killer cell inhibitory receptors (KIR) to recognize target cells. KIR binding to MHC class I molecules delivers an inhibitory signal, preventing NK cell activation and promoting self-tolerance.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Biology

Background:

  • Natural killer (NK) cells are crucial for innate immunity, selectively eliminating target cells lacking self-major histocompatibility complex (MHC) class I molecules.
  • NK cell-mediated cytotoxicity is regulated by a balance between activating and inhibitory receptors, with inhibitory receptors recognizing MHC class I molecules.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying killer cell inhibitory receptor (KIR) function in NK cell-mediated cytotoxicity.
  • To elucidate the role of SHP-1 tyrosine phosphatase in KIR-mediated inhibition and explore evolutionary convergence in inhibitory receptor signaling.

Main Methods:

  • Isolation and characterization of molecular clones for human killer cell inhibitory receptors (KIR).
  • Formation of soluble KIR-HLA-C complexes to study ligand binding.

Related Experiment Videos

  • Functional expression systems in human NK clones to assess KIR-mediated signaling.
  • Analysis of conserved motifs for SHP-1 recruitment and activation.

    • Main Results:

    • KIR molecules, comprising a family with varying Ig ectodomains and cytoplasmic tails, recognize and bind HLA-C molecules as autonomous receptors.
    • A single KIR can mediate both MHC class I recognition and deliver a dominant negative signal to NK cells.
    • Functional evidence implicates SHP-1 tyrosine phosphatase in KIR-mediated inhibition.
    • A conserved motif for SHP-1 recruitment in KIR and mouse Ly-49 receptors suggests evolutionary convergence, leading to the identification of other inhibitory receptors.

    Conclusions:

    • KIR receptors play a critical role in NK cell self-recognition and inhibition through direct interaction with MHC class I molecules.
    • SHP-1 is a key mediator of KIR-induced NK cell inhibition, highlighting a conserved signaling pathway.
    • The identification of a conserved inhibitory motif expands our understanding of immune receptor regulation and evolutionary adaptation.