title: Cutting edge: inhaled antigen upregulates retinaldehyde dehydrogenase in lung CD103+ but not plasmacytoid dendritic cells to induce Foxp3 de novo in CD4+ T cells and promote airway tolerance.
abstract: Dendritic cell (DC)-T cell interactions that underlie inducible/adaptive regulatory T cell generation and airway tolerance are not well understood. In this study, we show that mice lacking CD11c(hi) lung DCs, but containing plasmacytoid DCs (pDCs), fail tolerization with inhaled Ag and cannot support Foxp3 induction in vivo in naive CD4(+) T cells. CD103(+) DCs from tolerized mice efficiently induced Foxp3 in cocultured naive CD4(+) T cells but pDCs and lung macrophages failed to do so. CD103(+) DCs, but not pDCs or lung macrophages, upregulated the expression of retinaldehyde dehydrogenase 2 (aldh1a2), which is key for the production of retinoic acid, a cofactor for TGF-β for Foxp3 induction. Batf3(-/-) mice, selectively lacking CD103(+) DCs, failed tolerization by inhaled Ag. Collectively, our data show that pulmonary tolerance is dependent on CD103(+) DCs, correlating with their ability to upregulate aldh1a2, which can promote Foxp3 expression in T cells.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Khare
authors.forename: Nandini
authors.initials: N
authors.lastname: Krishnamoorthy
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Oriss
authors.forename: Mingjian
authors.initials: M
authors.lastname: Fei
authors.forename: Prabir
authors.initials: P
authors.lastname: Ray
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ray
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D039521:CD11c Antigen / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D007108:Immune Tolerance / Q000276:immunology; D039001:Integrin alpha Chains / Q000096:biosynthesis*; D008168:Lung / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D039521:CD11c Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D039001:Integrin alpha Chains; C091367:alpha E integrins; D000444:Aldehyde Dehydrogenase