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Chimeric NKG2D T Cells Require Both T Cell- and Host-Derived Cytokine Secretion and Perforin Expression to Increase Tumor Antigen Presentation and Systemic Immunity^1,2

Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756

Treatment of mice bearing established ovarian tumors with T cells expressing chimeric NKG2D receptors (chNKG2D) develop protective host immune responses to tumor Ags. In this study, the mechanisms that chNKG2D T cells require to induce host immunity against ovarian tumors and which of the host immune cells are involved in tumor elimination were determined. Treatment with chNKG2D T cells led to a sustained, increased IFN- production by host NK, CD4⁺, and CD8⁺ T cells in the spleen and at the tumor site and this continued for many weeks after T cell injection. Tumor Ag presentation was enhanced in chNKG2D T cell-treated mice, and there were greater numbers of tumor-specific T cells at the tumor site and in draining lymph nodes after treatment with chNKG2D T cells. The increase in host cell cytokine secretion and Ag presentation was dependent on chNKG2D T cell-derived perforin, IFN-, and GM-CSF. Host immune mechanisms were involved in tumor elimination because inhibition of tumor growth was limited in mice that lacked perforin, IFN-, NK cells, or T and B cells (Rag1^–/–). There was no role for host-derived GM-CSF or CD1-dependent NKT cells, because mice deficient in these were able to clear tumors as well as treated wild-type B6 mice. In summary, chNKG2D T cells required both cytotoxicity and cytokine secretion as well as the participation of host immune cells for development of a host antitumor immune response and complete efficacy.

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 This study was supported in part by grants from the Department of Microbiology and Immunology and the National Institutes of Health (Grants T32 AI07363 and CA130911). A.B. was supported by a John H. Copenhaver, Jr., and William H. Thomas, M.D., Fellowship from Dartmouth College.

² The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

³ Address correspondence and reprint requests to Dr. Charles L. Sentman, Department of Microbiology and Immunology, Dartmouth Medical School, 6W Borwell Building, One Medical Center Drive, Lebanon, NH 03756. E-mail address: charles.sentman{at}dartmouth.edu

⁴ Abbreviations used in this paper: chNKG2D, chimeric NKG2D; wtNKG2D, wild-type NKG2D.

⁵ The online version of this article contains supplemental material.

This article has been cited by other articles:

				A. Barber, A. Rynda, and C. L. Sentman Chimeric NKG2D Expressing T Cells Eliminate Immunosuppression and Activate Immunity within the Ovarian Tumor Microenvironment J. Immunol., December 1, 2009; 183(11): 6939 - 6947. [Abstract] [Full Text] [PDF]