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

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

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  • 1Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington 98109, USA.

Erratum in

  • Nat Immunol. 2006 Sep;7(9):1004.


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.

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