NKG2D performs two functions in invariant NKT cells: direct TCR-independent activation of NK-like cytolysis and co-stimulation of activation by CD1d

Eur J Immunol. 2011 Jul;41(7):1913-23. doi: 10.1002/eji.200940278. Epub 2011 Jun 6.


Invariant NKT cells are important in the activation and regulation of immune responses. They can also function as CD1d-restricted killer cells. However, the role of activating innate NK-cell receptors expressed on NKT cells in triggering cytolytic function is poorly characterized. Here, we initially confirmed that the cellular stress-ligand receptor NKG2D is expressed on CD4- NKT cells, whereas most CD4+ NKT cells lack this receptor. Interestingly, NKG2D+ NKT cells frequently expressed perforin, and both NKG2D and perforin localized at the site of contact with NKG2D ligand-expressing target cells. CD4- NKT cells degranulated in response to NKG2D engagement in a redirected activation assay independent of stimulation via their invariant TCR. NKT cells killed P815 cells coated with anti-NKG2D mAb and CD1d-negative K562 tumor target cells in an NKG2D-dependent manner. Furthermore, NKG2D engagement co-stimulated TCR-mediated NKT-cell activation in response to endogenous CD1d-presented ligands or suboptimal levels of anti-CD3 triggering. These data indicate that the CD4- subset of human NKT cells can mediate direct lysis of target cells via NKG2D engagement independent of CD1d, and that NKG2D also functions as a co-stimulatory receptor in these cells. NKG2D thus plays both a direct and a co-stimulatory role in the activation of NKT cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antigens, CD1d / immunology*
  • CD4 Antigens / biosynthesis
  • CD4 Antigens / genetics
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic*
  • Flow Cytometry
  • Humans
  • K562 Cells
  • Lymphocyte Activation*
  • Mice
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism*
  • Natural Killer T-Cells / immunology*
  • Perforin / metabolism
  • Receptors, Antigen, T-Cell / immunology


  • Antibodies, Monoclonal
  • Antigens, CD1d
  • CD4 Antigens
  • KLRK1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Antigen, T-Cell
  • Perforin