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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900438v1 183/5/3053    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Baba, T. Articles by Mukaida, N. PubMed PubMed Citation Articles by Baba, T. Articles by Mukaida, N.

Crucial Contribution of Thymic Sirp⁺ Conventional Dendritic Cells to Central Tolerance against Blood-Borne Antigens in a CCR2-Dependent Manner

Tomohisa Baba^*, Yasunari Nakamoto and Naofumi Mukaida^1,*

^* Division of Molecular Bioregulation, Cancer Research Institute and Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan

Thymic dendritic cells (DCs) as well as thymic epithelial cells are presumed to be major sentinels in central tolerance by inducing the apoptosis of autoreactive T progenitor cells. The thymic DC population is composed of heterogeneous subsets including CD11c⁺B220⁺ plasmacytoid DCs, CD11c⁺B220^–CD8⁺ signal regulatory protein (Sirp)^– and CD11c⁺B220^–CD8^–Sirp⁺ conventional DCs (cDCs). However, the distinctive role of each DC subset remains undefined. We show herein that Sirp⁺ cDCs, a minor subpopulation, was disseminated in the thymic cortical area with some of them uniquely localized inside perivascular regions and nearby small vessels in the thymus. The Sirp⁺ but not Sirp^– cDC subset can selectively capture blood-circulating Ags. Moreover, in CCR2-deficient mice, the thymic Sirp⁺ cDC subset, but not other thymic cell components, was moderately decreased especially in the perivascular regions. Concomitantly, these mice exhibited a modest impairment in intrathymic negative selection against blood-borne Ags, with the reduced capacity to uptake blood-borne Ags. Given their intrathymic cortical localization, CD11c⁺B220^–CD8^–Sirp⁺ cDCs can have a unique role in the development of central tolerance against circulating peripheral Ags, at least partially in a CCR2-dependent manner.

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 Address correspondence and reprint requests to Dr. Naofumi Mukaida, Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan. E-mail address: naofumim{at}kenroku.kanazawa-u.ac.jp

² Abbreviations used in this paper: mTEC, medullary thymic epithelial cell; DC, dendritic cell; Sirp, signal regulatory protein ; pDC, plasmacytoid DC; cDC, conventional DC; WT, wild type; Col IV, type IV collagen; FCM, flow cytometry; CMFDA, 5-chloromethylfluorescien diacetate; Cyt D, cytochalasin D; FSC, forward scatter; SSC, side scatter; DP, double positive.

³ The online version of this article contains supplemental material.