title: "Alternatively activated" dendritic cells preferentially secrete IL-10, expand Foxp3+CD4+ T cells, and induce long-term organ allograft survival in combination with CTLA4-Ig.
abstract: In this study, we propagated myeloid dendritic cells (DC) from BALB/c (H2(d)) mouse bone marrow progenitors in IL-10 and TGF-beta, then stimulated the cells with LPS. These "alternatively activated" (AA) DC expressed lower TLR4 transcripts than LPS-stimulated control DC and were resistant to maturation. They expressed comparatively low levels of surface MHC class II, CD40, CD80, CD86, and programmed death-ligand 2 (B7-DC; CD273), whereas programmed death-ligand 1 (B7-H1; CD274) and inducible costimulatory ligand expression were unaffected. AADC secreted much higher levels of IL-10, but lower levels of IL-12p70 compared with activated control DC. Their poor allogeneic (C57BL/10; B10) T cell stimulatory activity and ability to induce alloantigen-specific, hyporesponsive T cell proliferation was not associated with enhanced T cell apoptosis. Increased IL-10 production was induced in the alloreactive T cell population, wherein CD4+Foxp3+ cells were expanded. The AADC-expanded allogeneic CD4+CD25+ T cells showed enhanced suppressive activity for T cell proliferative responses compared with freshly isolated T regulatory cells. In vivo migration of AADC to secondary lymphoid tissue was not impaired. A single infusion of BALB/c AADC to quiescent B10 recipients induced alloantigen-specific hyporesponsive T cell proliferation and prolonged subsequent heart graft survival. This effect was potentiated markedly by CTLA4-Ig, administered 1 day after the AADC. Transfer of CD4+ T cells from recipients of long-surviving grafts (>100 days) that were infiltrated with CD4+Foxp3+ cells, prolonged the survival of donor-strain hearts in naive recipients. These data enhance insight into the regulatory properties of AADC and demonstrate their therapeutic potential in vascularized organ transplantation.
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
authors.forename: Yuk Yuen
authors.initials: YY
authors.lastname: Lan
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Wang
authors.forename: Giorgio
authors.initials: G
authors.lastname: Raimondi
authors.forename: Wenhan
authors.initials: W
authors.lastname: Wu
authors.forename: Bridget L
authors.initials: BL
authors.lastname: Colvin
authors.forename: An
authors.initials: A
authors.lastname: de Creus
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D017209:Apoptosis; D015704:CD4 Antigens / Q000032:analysis; D002465:Cell Movement; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation*; D051858:Forkhead Transcription Factors / Q000032:analysis; D006084:Graft Rejection / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D018796:Immunoconjugates / Q000008:administration & dosage*; D016753:Interleukin-10 / Q000378:metabolism / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000949:Histocompatibility Antigens Class II; D018796:Immunoconjugates; D008070:Lipopolysaccharides; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D000069594:Abatacept