Impaired tumor rejection by memory CD8 T cells in mice with NKG2D dysfunction

Int J Cancer. 2012 Oct 1;131(7):1601-10. doi: 10.1002/ijc.26191. Epub 2011 Aug 1.


Cytotoxic T cells are important effectors for robust antitumor immune responses. However, tumor-infiltrating CD8 T cells are often functionally impaired. Insufficient antitumor activity of CD8 T cells can be due to a lack of costimulatory signals. NKG2D is such a costimulatory receptor on CD8 T cells that facilitates immunorecognition of stressed and malignant cells, promotes tumor rejection by NK and CD8 T cells and contributes to immunosurveillance of spontaneous malignancies. Previous reports suggested an involvement of NKG2D in establishing CD8 T cell-mediated antitumor memory. However, the significance of NKG2D for the generation and effector phase of memory CD8 T cell responses is largely unknown. To address these issues, we made use of a transgenic mouse model (H2-K(b)-MICA mice) where the human NKG2D ligand MICA is ubiquitously and constitutively expressed resulting in a severe dysfunction of NKG2D. Both, ovalbumin (OVA)-specific (H2-K(b)/OVA(257-264)) memory CD8 T cells arisen from the endogenous T cell pool and adoptively transferred OVA-specific OT-I memory cells were unable to control growth of an OVA-expressing lymphoma in H2-K(b)-MICA mice. While expansion of memory T cells in these mice on antigen challenge was not different from controls, CD8 memory T cells of H2-K(b)-MICA mice did not effectively eliminate tumor cells in vivo. Altogether, our data suggest that NKG2D has no major role in the generation and expansion of memory CD8 T cells, but rather substantially enhances the cytolytic effector responses of reactivated memory T cells and thereby contributes to an efficacious tumor rejection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, Neoplasm / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic / immunology
  • Female
  • Humans
  • Immunologic Memory*
  • Mice
  • Mice, Transgenic
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism*
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Neoplasms / therapy


  • Antigens, Neoplasm
  • Klrk1 protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily K