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

Nature Immunology volume 7, pages 755–762 (2006)Cite this article

A Corrigendum to this article was published on 01 September 2006

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Abstract

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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Figure 1: Increased frequency of NKG2D+CD4+ T cells in patients with tumors.
Figure 2: MIC-driven population expansion of anti-CD3-induced NKG2D+CD4+ T cells and association of NKG2D with DAP10.
Figure 3: MIC-dependent costimulation and inhibition, respectively, of NKG2D+ and NKG2D−CD4+ T cell proliferation.
Figure 4: Inhibition of T cell proliferation is independent of ligand type and is induced by serum from patients with sMICA+ tumors.
Figure 5: T cell proliferation is inhibited by a soluble factor produced by NKG2D+CD4+ T cells.
Figure 6: NKG2D+CD4+ T cell cytokine profiles and production of FasL that mediates Fas-dependent responder T cell growth arrest.
Figure 7: NKG2D+CD4+ T cell clones stimulated with autologous MIC+ ovarian tumor cells produce FasL, which promotes HT-29 tumor cell death.
Figure 8: NKG2D-dependent FasL production by NKG2D+CD8+ T cells and negative paracrine regulation of CD8+ T cell growth.

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  • 20 June 2006

    In the version of this article initially published, the key and figure labels for Figure 8c are incorrect. The gray bars are C1R–A2–MICA–M27, the filled bars are C1R–A2–M27, and the cells are CD8+ (not CD4+). The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank G. Venkataraman for help with real-time PCR, and C. Yee for T cell clones. Supported by the Avon Foundation Breast Cancer Immunotherapy Research Initiative and the National Institutes of Health (AI30581 and AI52319).

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

    Veronika Groh, Kimberly Smythe, Zhenpeng Dai & Thomas Spies

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Correspondence to Veronika Groh or Thomas Spies.

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Supplementary information

Supplementary Fig. 1

Frequency distributions of NKG2D+CD4+ T cells. (PDF 448 kb)

Supplementary Fig. 2

Expression of CD25, CD45RO and HLA-DR by NKG2D+CD4+ T (PDF 176 kb)

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Groh, V., Smythe, K., Dai, Z. et al. Fas ligand–mediated paracrine T cell regulation by the receptor NKG2D in tumor immunity. Nat Immunol 7, 755–762 (2006). https://doi.org/10.1038/ni1350

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