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Novel Subset of CD8⁺ Dendritic Cells Localized in the Marginal Zone Is Responsible for Tolerance to Cell-Associated Antigens¹

Chun-Hong Qiu^2,*, Yasunobu Miyake^2,*, Hitomi Kaise^*, Hiroshi Kitamura, Osamu Ohara^, and Masato Tanaka^3,*

^* Laboratory for Innate Cellular Immunity and Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology, Kanagawa, Japan; and Department of Human Genome Research, Kazusa DNA Research Institute, Chiba, Japan

Apoptotic cell clearance by dendritic cells (DCs) plays a crucial role in the maintenance of self-tolerance. In spleen, CD8⁺ DCs are thought to be responsible for this phenomenon by phagocytosing circulating apoptotic cells. However, as CD8⁺ DCs are believed to be predominantly localized in the T cell zone, it remains unclear how these DCs phagocytose blood-borne apoptotic cells accumulated in the marginal zone (MZ). In this study, we identified a subpopulation of CD8⁺ DCs responsible for tolerance induction to cell-associated Ags. Among splenic CD8⁺ DCs, the CD103⁺,CD207⁺ subset was preferentially localized in the MZ and dominantly phagocytosed blood-borne apoptotic cells. After phagocytosis of apoptotic cells, this DC subset migrated into the T cell zone for cross-presentation of cell-associated Ags. Stimulation of TLRs induced the disappearance of this DC subset. Consequently, CD8⁺ DCs neither phagocytosed injected apoptotic cells nor presented cell-associated Ags in mice treated with TLR ligands. Transient ablation of this DC subset by cytochrome c injection resulted in a failure of tolerance induction to cell-associated Ags, indicating that this DC subset is essential for tolerance induction by apoptotic cell clearance.

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 in a part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology in Japan and from the Sankyo Foundation of Life Science.

² C.-H.Q. and Y.M. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Masato Tanaka, Laboratory for Innate Cellular Immunity, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan. E-mail address: mtanaka{at}rcai.riken.jp

⁴ Abbreviations used in this paper: DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; LN, lymph node; MOG, myelin oligodendrocyte glycoprotein; MMM, marginal metallophilic macrophage; MZ, marginal zone; MZM, marginal zone macrophage; PS, phosphatidylserine.

⁵ The online version of this article contains supplemental material.

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