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DC-SIGN(+) Macrophages Control the Induction of Transplantation Tolerance

 Patricia Conde  ;  Mercedes Rodriguez  ;  William van der Touw  ;  Ana Jimenez  ;  Matthew Burns  ;  Jennifer Miller  ;  Manisha Brahmachary  ;  Hui-ming Chen  ;  Peter Boros  ;  Francisco Rausell-Palamos  ;  Tae Jin Yun  ;  Paloma Riquelme  ;  Alberto Rastrojo  ;  Begoña Aguado  ;  Joan Stein-Streilein  ;  Masato Tanaka  ;  Lan Zhou  ;  Junfeng Zhang  ;  Todd L. Lowary  ;  Florent Ginhoux  ;  Chae Gyu Park  ;  Cheolho Cheong  ;  Joshua Brody  ;  Shannon J. Turley  ;  Sergio A. Lira  ;  Vincenzo Bronte  ;  Siamon Gordon  ;  Peter S. Heeger  ;  Miriam Merad  ;  James Hutchinson 
 IMMUNITY, Vol.42(6) : 1143-1158, 2015 
Journal Title
Issue Date
Animals ; CD8-Positive T-Lymphocytes/immunology ; Cell Adhesion Molecules/genetics ; Cell Adhesion Molecules/metabolism* ; Cells, Cultured ; Forkhead Transcription Factors/metabolism ; Graft Rejection/etiology ; Graft Rejection/prevention & control* ; Heart Transplantation* ; Immune Tolerance ; Interleukin-10/metabolism ; Lectins, C-Type/genetics ; Lectins, C-Type/metabolism* ; Macrophage Colony-Stimulating Factor/metabolism ; Macrophages/immunology* ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular Targeted Therapy ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/metabolism* ; Signal Transduction ; T-Lymphocytes, Regulatory/immunology* ; Toll-Like Receptor 4/metabolism ; Transplantation Tolerance ; Up-Regulation
Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8(+) T cell immunity and promoted CD4(+)Foxp3(+) Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN(+) suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Park, Chae Gyu(박채규) ORCID logo https://orcid.org/0000-0003-1906-1308
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