NKG2D regulates production of soluble TRAIL by ex vivo expanded human γδ T cells

Authors

  • Pouneh Dokouhaki,

    1. Toronto General Research Institute, University Health Network, Toronto, Canada
    Current affiliation:
    1. Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Canada
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    • These authors contributed equally to this work.

  • Nicholas W. Schuh,

    1. Toronto General Research Institute, University Health Network, Toronto, Canada
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    • These authors contributed equally to this work.

  • Betty Joe,

    1. Toronto General Research Institute, University Health Network, Toronto, Canada
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  • Christopher A. D. Allen,

    1. Toronto General Research Institute, University Health Network, Toronto, Canada
    2. Institute of Medical Sciences, University of Toronto, Toronto, Canada
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  • Sandy D. Der,

    1. Toronto General Research Institute, University Health Network, Toronto, Canada
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  • Ming-Sound Tsao,

    1. Toronto General Research Institute, University Health Network, Toronto, Canada
    2. Ontario Cancer Institute, University Health Network, Toronto, Canada
    3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
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  • Li Zhang

    Corresponding author
    1. Toronto General Research Institute, University Health Network, Toronto, Canada
    2. Institute of Medical Sciences, University of Toronto, Toronto, Canada
    3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
    4. Department of Immunology, University of Toronto, Toronto, Canada
    • Full correspondence: Dr. Li Zhang, Toronto General Research Institute, University Health Network, TMDT, 2–807, 101 College St., Toronto, ON M5G 1L7, Canada

      Fax: +1-416-581-7515

      e-mail: lzhang@uhnresearch.ca

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Abstract

Soluble TRAIL (sTRAIL) can be produced by myeloid-derived cells to kill cancer cells. Whether this mechanism is used by T cells, and if so, how sTRAIL production is regulated, remains unclear. Our previous studies showed that ex vivo expanded human γδ T cells express TRAIL and NK receptor group 2 (R2), member D (NKG2D), and possess potent anticancer activities both in vitro and in vivo. Here, we investigated in greater detail the mechanisms by which γδ T cells utilize TRAIL and NKG2D to kill lung cancer cells. We demonstrate that human lung cancer cells express TRAIL R2 and NKG2D ligands. Blocking TRAIL or NKG2D during γδ T-cell-lung cancer cell co-cultures significantly reduced γδ T-cell-mediated cytotoxicity. Cross-linking NKG2D with anti-NKG2D antibody to mimic ligand binding promoted γδ T cells to produce sTRAIL, which induced apoptosis in lung cancer cells through TRAIL R2. Either neutralizing sTRAIL or blocking lung cancer cell TRAIL R2 significantly reduced γδ T-cell-mediated cytotoxicity to lung cancer cells. This study demonstrates that γδ T cells can mediate anticancer immunity via NKG2D-regulated production of sTRAIL.

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