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Naive Mouse Macrophages Become Activated following Recognition of L5178Y Lymphoma Cells via Concurrent Ligation of CD40, NKG2D, and CD18 Molecules¹

Ilia N. Buhtoiarov^2,*,, Alexander L. Rakhmilevich^*,, Lewis L. Lanier^¶, Erik A. Ranheim^, and Paul M. Sondel^2,*,,

^* Department of Human Oncology, Department of Pediatrics, Department of Pathology and Laboratory Medicine and the Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53792; and ^¶ Department of Microbiology and Immunology and the Cancer Research Institute, University of California San Francisco, CA 94143

Under different circumstances, tumors can inhibit or activate macrophage (M) effector functions. We studied the mechanisms of tumor-M interactions leading to M activation. The results show that L5178Y mouse T cell lymphoma cells can prime naive mouse M to subsequent LPS stimulation, resulting in increased NO production and antilymphoma effects in vitro. L5178Y cells, but not naive splenocytes, primed M to ligation of TLR4 but not TLR9. L5178Y-primed M incubated with LPS showed down-regulation of CD40 and up-regulation of NKG2D expression. Although L5178Y T cell lymphoma cells primed naive mouse M, several other mouse and human cells lines failed to prime mouse M. Neither L5178Y-conditioned supernatants nor coculture of M and L5178Y cells in Transwells resulted in priming, indicating that direct L5178Y cell-M contact was needed. Several receptor-ligand pairs are reciprocally expressed on M and L5178Y cell membranes and can be potentially involved in M priming. Of these, the CD40-CD154 pair played the most important role, as blocking the interaction of these molecules substantially reduced in vitro M priming. Furthermore, simultaneous blocking of interactions between CD40-CD154, NKG2D-H60, and CD18-ICAM-1/2 led to complete abrogation of M-mediated NO secretion and complete inhibition of M-mediated tumor cell cytostasis. The priming of M to LPS with L5178Y cells was also observed in vivo. These results suggest that contact with certain tumor cells via CD40, NKG2D, and CD18 molecules on the M may facilitate M-mediated antitumor immune surveillance.

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 National Institutes of Health Grants CA87025 and CA032685 (to P.M.S.) and AI066897 (to L.L.L.), grants from the Midwest Athletes against Childhood Cancer Fund (to P.M.S., A.L.R., and I.N.B.), and a grant from the University of Wisconsin Cure Kids Cancer Coalition (to I.N.B. and P.M.S.). L.L.L. is an American Cancer Society Research Professor.

² Address correspondence and reprint requests to Dr. Paul M. Sondel and Dr. Ilia N. Buhtoiarov, Department of Human Oncology, University of Wisconsin, K4/448 Clinical Science Center or K4/440 Clinical Science Building, 600 Highland Avenue, Madison, WI 53792. E-mail addresses: pmsondel{at}humonc.wisc.edu and buhtoiarov{at}humonc.wisc.edu

³ Abbreviations used in this paper: M, macrophage; PC, peritoneal cell; PF, paraformaldehyde fixed; TW, Transwell; MHC-I/II, MHC class I/II.