title: Transfer of regulatory properties from tolerogenic to proinflammatory dendritic cells via induced autoreactive regulatory T cells.
abstract: Infectious tolerance is a term generally assigned to the process through which regulatory T cells (Tregs) transfer immunoregulatory properties to other T cells. In this study, we demonstrated that a similar process applies to human dendritic cells (DCs), albeit through a different mechanism. We induced and cloned proinsulin-specific Tregs using tolerogenic DCs and investigated mechanisms by which induced Ag-specific regulatory T cells (iaTregs) endorse the suppressive effects. iaTregs expressed FOXP3, programmed death-1, and membrane-bound TGF-β and upregulated IL-10 and CTLA-4 after stimulation with the cognate Ag. The iaTregs suppressed effector T cells only when both encountered the cognate Ags on the same APCs (linked suppression). This occurred independently of IL-10, TGF-β, programmed death-1, or CTLA-4. Instead, iaTregs used a granzyme B-mediated mechanism to kill B cells and monocytes, whereas proinflammatory DCs that resisted being killed were induced to upregulate the inhibitory receptors B7 (family) homolog 3 and ICOS ligand. These re-educated mature monocyte-derived dendritic cells (mDCs) suppressed effector T cells and induced IL-10-producing cells from the naive T cell pool. Our data indicated that human tolerogenic DCs confer infectious tolerance by inducing Ag-specific Tregs, which, in turn, re-educate proinflammatory mature DCs into DCs with regulatory properties.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Fleur S
authors.initials: FS
authors.lastname: Kleijwegt
authors.forename: Sandra
authors.initials: S
authors.lastname: Laban
authors.forename: Gaby
authors.initials: G
authors.lastname: Duinkerken
authors.forename: Antoinette M
authors.initials: AM
authors.lastname: Joosten
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.forename: Tatjana
authors.initials: T
authors.lastname: Nikolic
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000502:physiology; D002999:Clone Cells; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D059811:HLA-DRB1 Chains / Q000502:physiology; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D011384:Proinsulin / Q000096:biosynthesis / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D018984:Epitopes, T-Lymphocyte; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; C508017:IL2RA protein, human; D018836:Inflammation Mediators; D053645:Interleukin-2 Receptor alpha Subunit; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D002762:Cholecalciferol; D011384:Proinsulin