title: Activation of dendritic cells via TLR7 reduces Foxp3 expression and suppressive function in induced Tregs.
abstract: Exogenous and endogenous RNA ligands of Toll-like receptor (TLR) 7 which are present during viral infection or autoimmune diseases such as systemic lupus erythematosus (SLE) directly activate DCs and B cells and thus support the generation of effector T and B lymphocytes. However, the generation of effective antiviral or autoreactive adaptive immune responses requires blocking of immunosuppression by Tregs. In this study, we show that TLR7 ligands reduce the number of Tregs generated de novo from naïve murine T cells in vitro and in vivo. In the presence of TLR7-activated splenic DCs, Foxp3 was transiently induced in naïve T cells by TGF-β but was downregulated at later time points. Neutralization experiments revealed that loss of Foxp3 after initial induction was mostly dependent on IL-6 produced in the DC-T-cell cocultures containing TLR7 ligands. Thus, under the influence of TLR7 ligands fewer Tregs were generated and these expressed lower levels of Foxp3 correlating with a reduced capacity to suppress responder T-cell proliferation. Thus, we provide evidence that TLR7 ligands affect Treg-dependent immune regulation and may thereby contribute to the development of autoimmune diseases such as systemic lupus erythematosus.
authors.affiliation: II. Medical Department, Klinikum rechts der Isar, Technical University Munich, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Hackl
authors.forename: Jakob
authors.initials: J
authors.lastname: Loschko
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Reindl
authors.forename: Anne B
authors.initials: AB
authors.lastname: Krug
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007108:Immune Tolerance; D015850:Interleukin-6 / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012313:RNA / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015850:Interleukin-6; D008024:Ligands; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D016212:Transforming Growth Factor beta; D012313:RNA