Fas-ligand-mediated paracrine T cell regulation by the receptor NKG2D in tumor immunity

Nat Immunol. 2006 Jul;7(7):755-62. doi: 10.1038/ni1350. Epub 2006 May 28.


Tumor-associated ligands of the activating NKG2D receptor can effectively stimulate T cell responses at early but not late stages of tumor growth. In late-stage human tumor settings, we observed MIC-driven proliferation of NKG2D(+)CD4(+) T cells that produced the cytokine Fas ligand (FasL) as a result of NKG2D costimulation but were themselves protected from Fas-mediated growth arrest. In contrast, FasL suppressed proliferation of T cells in vitro that did not receive NKG2D costimulation. Similar observations with normal peripheral blood NKG2D(+)CD8(+) T cells demonstrated unrecognized NKG2D-mediated immune functions, whereby FasL release promotes tumor cell death and NKG2D costimulation prolongs T cell survival. These effects, beneficial in conditions of limited NKG2D ligand expression, may be counterweighed when massive expression and shedding of MIC occurs, such as in some late-stage tumors, that causes sustained NKG2D costimulation and population expansion of immunosuppressive T cells.

Publication types

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

MeSH terms

  • CD4-Positive T-Lymphocytes / chemistry
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Carcinoma / immunology
  • Carrier Proteins / analysis
  • Cytokines / metabolism
  • Cytoplasmic Granules / metabolism
  • Fas Ligand Protein
  • GPI-Linked Proteins
  • Gene Expression Regulation
  • Histocompatibility Antigens Class I / analysis
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lymphocytes, Tumor-Infiltrating / chemistry
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Melanoma / immunology
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / physiology*
  • Membrane Proteins / analysis
  • NK Cell Lectin-Like Receptor Subfamily K
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Paracrine Communication / physiology*
  • Receptors, Immunologic / analysis
  • Receptors, Immunologic / physiology*
  • Receptors, Natural Killer Cell
  • Solubility
  • Tumor Necrosis Factors / biosynthesis
  • Tumor Necrosis Factors / physiology*


  • Carrier Proteins
  • Cytokines
  • FASLG protein, human
  • Fas Ligand Protein
  • GPI-Linked Proteins
  • Histocompatibility Antigens Class I
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • KLRK1 protein, human
  • MHC class I-related chain A
  • Membrane Glycoproteins
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • RAET1E protein, human
  • RAET1G protein, human
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • Tumor Necrosis Factors
  • ULBP1 protein, human
  • ULBP2 protein, human
  • ULBP3 protein, human