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* Medical Top Track Program, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan;
Laboratory for Cellular Physiology and Immunology, Rockefeller University, New York, NY 10065;
Institute for Systems Biology, Seattle, WA 98103; and
Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
Dendritic cells (DCs) are professional APCs that can control immune responses against self and altered self, typically foreign, determinants. DCs can be divided into several subsets, including CD8
+ and CD8– DCs. These subsets possess specific functions. For example, mouse splenic CD8+, but not CD8– DCs selectively take up dying cells and cross-present cell-associated Ags to naive T cells. In this study, we identified genes that were more expressed in CD8+ than CD8– DCs by microarray analysis. Only one of these genes, when the extracellular domains were linked to human IgG Fc domain, could bind to late apoptotic or necrotic cells. This gene was a new member of the triggering receptor expressed on myeloid cells (Trem) family, Trem-like 4 (Treml4). Treml4 mRNA and protein, the latter detected with a new mAb, were predominantly expressed in spleen. Treml4, like other Trem family members, could associate with the adaptor molecule DNAX activation protein 12 kDa, but neither DNAX activation protein 10 kDa nor FcR
. Consistent with the microarray data, we confirmed that Treml4 protein was more expressed on CD8+ than CD8– DCs, and we also found that Treml4 was expressed at high levels on splenic macrophages in spleen, particularly red pulp and marginal metallophilic macrophages. In addition, Treml4 expression on DCs was not changed after maturation induced by TLR ligands. Thus, Treml4 is a new Trem family molecule that is abundantly expressed on CD8+ DCs and subsets of splenic resident macrophages, and can recognize dead cells by different types of phagocytes in spleen.
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1 This work was supported by National Institutes of Health Grant AI13013 (to R.M.S.) and in part by the Program for Improvement of Research Environment for Young Researchers from Special Coordination Funds for Promoting Science and Technology commissioned by the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Grant-in-Aid for Young Scientists (19890063 and 20790299, to H.H.) from Ministry of Education, Culture, Sports, Science, and Technology of Japan. H.H. was a Japan Society for the Promotion of Science Postdoctoral Fellow for Research Abroad.
2 Address correspondence and reprint requests to Dr. Ralph M. Steinman, Laboratory of Cellular Immunology and Physiology, Rockefeller University, New York, NY 10065; E-mail address: steinma{at}rockefeller.edu or Dr. Hiroaki Hemmi, Medical Top Track Program, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan; E-mail address: hemmi.mtt{at}mri.tmd.ac.jp
3 Abbreviations used in this paper: DC, dendritic cell; DAP10, DNAX activation protein 10 kDa; DAP12, DNAX activation protein 12 kDa; Flt3L, Fms-like tyrosine kinase 3 ligand; HEK, human embryonic kidney; Mertk, Mer tyrosine kinase; PI, propidium iodide; poly(I:C), polyinosine-polycytidylic acid; Trem, triggering receptor expressed on myeloid cells; Treml4, Trem-like 4; SIGN-R1, specific intracellular adhesion molecule-grabbing nonintegrin receptor 1.
4 The online version of this article contains supplemental material.
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