title: Mechanisms underlying blockade of allograft acceptance by TLR ligands.
abstract: Immune activation via TLRs is known to prevent transplantation tolerance in multiple animal models. To investigate the mechanisms underlying this barrier to tolerance induction, we used complementary murine models of skin and cardiac transplantation in which prolonged allograft acceptance is either spontaneous or pharmacologically induced with anti-CD154 mAb and rapamycin. In each model, we found that prolonged allograft survival requires the presence of natural CD4(+)Foxp3(+) T regulatory cells (Tregs), and that the TLR9 ligand CpG prevents graft acceptance both by interfering with natural Treg function and by promoting the differentiation of Th1 effector T cells in vivo. We further demonstrate that although Th17 cells differentiate from naive alloreactive T cells, these cells do not arise from natural Tregs in either CpG-treated or untreated graft recipients. Finally, we show that CpG impairs natural Treg suppressor capability and prevents Treg-dependent allograft acceptance in an IL-6-independent fashion. Our data therefore suggest that TLR signals do not prevent prolonged graft acceptance by directing natural Tregs into the Th17 lineage or by using other IL-6-dependent mechanisms. Instead, graft destruction results from the ability of CpG to drive Th1 differentiation and interfere with immunoregulation established by alloreactive natural CD4(+)Foxp3(+) Tregs.
authors.affiliation: Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Paige M
authors.initials: PM
authors.lastname: Porrett
authors.forename: Xueli
authors.initials: X
authors.lastname: Yuan
authors.forename: David F
authors.initials: DF
authors.lastname: LaRosa
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Walsh
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Yang
authors.forename: Wenda
authors.initials: W
authors.lastname: Gao
authors.forename: Peiying
authors.initials: P
authors.lastname: Li
authors.forename: Jidong
authors.initials: J
authors.lastname: Zhang
authors.forename: Javeed M
authors.initials: JM
authors.lastname: Ansari
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Maria
authors.initials: M
authors.lastname: Koulmanda
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016038:Skin Transplantation / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D051193:Toll-Like Receptors; C453101:carboxyphenylglycine; D005998:Glycine