title: CD8+ CD205+ splenic dendritic cells are specialized to induce Foxp3+ regulatory T cells.
abstract: 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-beta- 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-beta. CD8(+)CD205(+) DCs preferentially express TGF-beta, and the induction of Treg by these DCs in vitro is blocked by neutralizing Ab to TGF-beta. In contrast, CD8(-)DCIR2(+) DCs better induce Foxp3(+) Treg when exogenous TGF-beta 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-beta. Targeting of Ag to these DCs might be useful for inducing Ag-specific Foxp3(+) Treg for treatment of autoimmune diseases, transplant rejection, and allergy.
authors.affiliation: Laboratory of Cellular Physiology and Immunology and Chris Browne Center of Immunology and Immune Disease, The Rockefeller University, New York, NY 10065, USA. yamazas@rockefeller.edu
authors.forename: Sayuri
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Diana
authors.initials: D
authors.lastname: Dudziak
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Heidkamp
authors.forename: Christopher
authors.initials: C
authors.lastname: Fiorese
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bonito
authors.forename: Kayo
authors.initials: K
authors.lastname: Inaba
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D010047:Ovalbumin / Q000276:immunology; D011956:Receptors, Cell Surface / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D016827:CD8 Antigens; C093569:DEC-205 receptor; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D010047:Ovalbumin