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Rat CD4⁺CD8⁺ Macrophages Kill Tumor Cells through an NKG2D- and Granzyme/Perforin-Dependent Mechanism¹

Tomohisa Baba^2,*, Sari Iwasaki^*, Takako Maruoka^*, Akira Suzuki^*, Utano Tomaru^*, Hitoshi Ikeda^*, Takashi Yoshiki^*, Masanori Kasahara^* and Akihiro Ishizu^3,

^* Department of Pathology, Hokkaido University Graduate School of Medicine and Department of Health Sciences, Division of Medical Technology, Hokkaido University School of Medicine, Sapporo, Japan

We previously identified a subpopulation of monocyte/macrophage lineage cells expressing both CD4 and CD8. This subpopulation was expanded in rat peripheral blood and spleen after immunization with adjuvants containing killed tuberculosis germs. CD4⁺CD8⁺ monocytes/macrophages obtained from preimmunized rats exhibited a Th1-type cytokine/chemokine profile, expressed high levels of Fas ligand, perforin, granzyme B, and NKR-P2 (rat ortholog of human NKG2D), and killed certain tumor cells. In the present study, we confirmed that CD4⁺CD8⁺ monocytes/macrophages are distinct from splenic dendritic cells (DCs) or IFN-producing killer DCs. In vitro cytotoxic assays revealed that CD4⁺CD8⁺ macrophages killed tumor cells in a cell-cell contact-dependent manner and that expression of the retinoic acid early transcript 1 (a ligand for NKG2D) made tumor cells susceptible to killing by CD4⁺CD8⁺ macrophages. Furthermore, inhibitors of granzyme and perforin significantly decreased cytotoxic activities of CD4⁺CD8⁺ macrophages. Consistent with these in vitro findings, preimmunization with adjuvants containing killed tuberculosis germs elevated the expression of granzyme B in tumor-infiltrating CD4⁺CD8⁺ macrophages and significantly inhibited the growth of inoculated tumor cells. Our current work demonstrates that CD4⁺CD8⁺ macrophages are a unique subpopulation of monocyte/macrophage lineage cells that kill tumor cells in an NKG2D- and granzyme/perforin-dependent mechanism.

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 grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

² Current address: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

³ Address correspondence and reprint requests to Dr. Akihiro Ishizu, Department of Health Sciences, Hokkaido University School of Medicine, Kita-12, Nishi-5, Kita-ku, Sapporo 060-0812, Japan. E-mail address: aishizu{at}med.hokudai.ac.jp

⁴ Abbreviations used in this paper: DC, dendritic cell; DCI, 3,4-dichloroisocoumarin; FCM, flow cytometry; IKDC, IFN-producing killer DC; RAET1, retinoic acid early transcript 1; EGFP, enhanced GFP; hIg, human Ig; DP, double positive.

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