"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.
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.
Lan
Yuk Yuen
YY
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
Wang
Zhiliang
Z
Raimondi
Giorgio
G
Wu
Wenhan
W
Colvin
Bridget L
BL
de Creus
An
A
Thomson
Angus W
AW
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
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