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Inhibition of Tumor Growth by NK1.1⁺ Cells and CD8⁺ T Cells Activated by IL-15 through Receptor β/Common Signaling in trans¹

Jesse Rowley^*, Archana Monie^*, Chien-Fu Hung^*, and T.-C. Wu^2,*,,,

Department of ^* Pathology, Department of Obstetrics and Gynecology, Department of Molecular Microbiology and Immunology, and Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231

IL-15 is an important cytokine involved in the survival and function of CD8⁺ T cells and NK cells. IL-15 can be presented by IL-15R (IL-15RA) to bind with the shared IL-2/IL-15Rβ and common -chains, which activate signaling pathways on NK cells and CD8⁺ T cells. In the present study, we characterized the function of trans-presented IL-15 on NK cells and CD8⁺ T cells using TC-1 tumor cells transduced with a retrovirus encoding IL-15 linked to IL-15RA (IL-15/IL-15RA). We demonstrated that the expression of IL-15/IL-15RA on TC-1 cells led to increased percentages of tumor-infiltrating NK cells, NKT cells, and CD8⁺ T cells, resulting in the inhibition of tumor growth in challenged mice. Additionally, in vivo Ab depletion experiments demonstrated that NK1.1⁺ cells and CD8⁺ T cells were important in this inhibition of tumor growth. Furthermore, this accumulation of immune cells and inhibition of tumor growth was abolished by a single amino acid mutation in the common -chain binding site on IL-15. We also observed that IL-15/IL-15RA-transduced TC-1 cells led to the activation of STAT5 in NK and CD8⁺ T cells in trans, which was abolished in the mutated IL-15/IL-15RA-transduced TC-1 cells. Taken together, our data suggest that common -chain binding-dependent activation of the shared IL-15/IL-2Rβ/common signaling pathway may play an important role in the activation of NK cells and CD8⁺ T cells, resulting in IL-15/IL-15RA trans-presentation-mediated inhibition of tumor growth.

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 work was supported by the National Cancer Institute SPOREs (Specialized Programs of Research Excellence) in Cervical Cancer Grants P50 CA098252 and 1 RO1 CA114425-01.

² Address correspondence and reprint requests to Dr. T.-C. Wu, Department of Pathology, The Johns Hopkins University School of Medicine, CRB II Room 309, 1550 Orleans Street, Baltimore, MD 21231. E-mail address: wutc{at}jhmi.edu

³ Abbreviations used in this paper: IL-15RA, IL-15R; _c, common ; IL2SP, IL-2 signal peptide; IRES, internal ribosomal entry site; MOSEC, murine ovarian surface epithelial carcinoma; TIL, tumor-infiltrating lymphocyte.

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