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CD8⁺CD205⁺ Splenic Dendritic Cells Are Specialized to Induce Foxp3⁺ Regulatory T Cells¹

Sayuri Yamazaki^2,3,*, Diana Dudziak^2,,, Gordon F. Heidkamp^,, Christopher Fiorese^*, Anthony J. Bonito^*, Kayo Inaba^,¶, Michel C. Nussenzweig and Ralph M. Steinman^*

^* Laboratory of Cellular Physiology and Immunology and Chris Browne Center of Immunology and Immune Disease and Laboratory of Molecular Immunology The Rockefeller University, New York, NY 10065; Nikolaus Fiebiger Center for Molecular Medicine, Department of Dermatology, Laboratory of Dendritic Cell Biology, University Hospital of Erlangen, Erlangen, Germany; Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University; and ^¶ JST, CREST, Yoshida-Konoe, Sakyo, Kyoto, Japan

Foxp3⁺CD25⁺CD4⁺ regulatory T cells (Treg) mediate immunological self-tolerance and suppress immune responses. A subset of dendritic cells (DCs) in the intestine is specialized to induce Treg in a TGF-β- and retinoic acid-dependent manner to allow for oral tolerance. In this study we compare two major DC subsets from mouse spleen. We find that CD8⁺ DEC-205/CD205⁺ DCs, but not the major fraction of CD8^– DC inhibitory receptor-2 (DCIR2)⁺ DCs, induce functional Foxp3⁺ Treg from Foxp3^– precursors in the presence of low doses of Ag but without added TGF-β. CD8⁺CD205⁺ DCs preferentially express TGF-β, and the induction of Treg by these DCs in vitro is blocked by neutralizing Ab to TGF-β. In contrast, CD8^–DCIR2⁺ DCs better induce Foxp3⁺ Treg when exogenous TGF-β is supplied. In vivo, CD8⁺CD205⁺ DCs likewise preferentially induce Treg from adoptively transferred, Ag-specific DO11.10 RAG^–/– Foxp3^–CD4⁺ T cells, whereas the CD8^–DCIR2⁺ DCs better stimulate natural Foxp3⁺ Treg. These results indicate that a subset of DCs in spleen, a systemic lymphoid organ, is specialized to differentiate peripheral Foxp3⁺ Treg, in part through the endogenous formation of TGF-β. Targeting of Ag to these DCs might be useful for inducing Ag-specific Foxp3⁺ Treg for treatment of autoimmune diseases, transplant rejection, and allergy.

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 Grant AI 051573, a program project grant from the Juvenile Diabetes Research Foundation, and German Research Foundation Grants DU-548/1-1 and DU-548/2-1 (to D.D.).

² S.Y. and D.D. are equal contributing first authors.

³ Address correspondence and reprint requests to Dr. Sayuri Yamazaki, Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065. E-mail address: yamazas{at}rockefeller.edu

⁴ Abbreviations used in this paper: Treg, regulatory T cell; DC, dendritic cell; DCIR2, DC inhibitory receptor-2; DEC, anti-DEC-205 mAb; FIR, Foxp3-internal ribosomal entry site-linked monomeric RFP; Iso, isotype-matched mAb; poly(I:C), polyinosinic-polycytidylic acid; RFP, red fluorescent protein; SA, streptavidin; 33D1, anti-DCIR2 mAb.

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