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J. Biol. Chem., Vol. 280, Issue 46, 38235-38241, November 18, 2005

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T Cells Gene-engineered with DAP12 Mediate Effector Function in an NKG2D-dependent and Major Histocompatibility Complex-independent Manner^*

Michele W. L. Teng1, Michael H. Kershaw2, Yoshihiro Hayakawa3, Loretta Cerutti, Stephen M. Jane, Phillip K. Darcy24, and Mark J. Smyth45

From the Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia and the Rotary Bone Marrow Research Laboratory, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia

NKG2D is an important activating/co-stimulatory receptor harnessed by NK and T cells in immune surveillance. In contrast to NK cells, T cells fail to express the activation-signaling molecule DAP12 even when activated and, therefore, ligation of NKG2D alone is insufficient to induce T cell cytolytic function. To test whether we could endow T cells with NK cell-like effector function, we have engineered DAP12 into T cells by retroviral transduction (T-DAP12). T-DAP12 cells were demonstrated to specifically secrete interferon- following receptor ligation and to mediate potent and specific lysis of the NKG2D ligand (NKG2D-L) (Rae-1) expressing MHC class I-deficient and class I-sufficient tumors. To circumvent the inability of T-DAP12 cells to proliferate following NKG2D ligation by Rae-1 expressing tumors, DAP12 was engineered into OT-1 cells with an endogenous T cell receptor specific for chicken ovalbumin peptide (amino acids 257–264). Importantly, following a period of proliferation through endogenous T cell receptor ligation, OT-1-DAP12 cells retained specificity against NKG2D-L expressing major histocompatibility complex class I-deficient tumor. In adoptive transfer experiments, T-DAP12 cells enhanced the survival of NK cell-depleted RAG-1-deficient mice inoculated with RMA-S-Rae-1 but not parental RMA-S tumors. Overall, this study demonstrated the significant potential of suppressing tumors and other cellular targets expressing NKG2D-L by endowing T cells with innate NK cell-like function.

Received for publication, May 16, 2005 , and in revised form, August 5, 2005.

^* The work was supported by funding from a National Health and Medical Research Council program grant, the Cancer Council of Victoria, and the Susan G. Komen Breast Cancer Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Melbourne International Fee Remission Scholarship and Melbourne International Research Scholarship.

² Supported by National Health and Medical Research Council R. D. Wright research fellowships.

³ Supported by a Cancer Research Institute post-doctoral fellowship.

⁴ These authors contributed equally to this work.

⁵ Supported by a National Health and Medical Research Council research fellowship. To whom correspondence should be addressed: Cancer Immunology Program, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St., East Melbourne, Victoria 8006, Australia. Tel.: 613-9656-3728; Fax: 613-9656-1411; E-mail: mark.smyth{at}petermac.org.

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