title: DC-SIGN(+) Macrophages Control the Induction of Transplantation Tolerance.
abstract: 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.
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Conde
authors.affiliation: Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rodriguez
authors.affiliation: Department of Oncological Sciences Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: William
authors.initials: W
authors.lastname: van der Touw
authors.affiliation: Department of Oncological Sciences Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Jimenez
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Burns
authors.affiliation: Department of Oncological Sciences Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Miller
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Brahmachary
authors.affiliation: Department of Oncological Sciences Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Hui-ming
authors.initials: HM
authors.lastname: Chen
authors.affiliation: Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Boros
authors.affiliation: Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Rausell-Palamos
authors.affiliation: Institut de Researches Cliniques de Montréal, Montréal, Québec H2W1R7, Canada.
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Yun
authors.affiliation: Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany.
authors.forename: Paloma
authors.initials: P
authors.lastname: Riquelme
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Rastrojo
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Aguado
authors.affiliation: Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Stein-Streilein
authors.affiliation: Laboratory of Immune Regulation, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Alberta Glycomics Centre and Department of Chemistry, University of Alberta, Edmonton T6G 2G2, Canada.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Alberta Glycomics Centre and Department of Chemistry, University of Alberta, Edmonton T6G 2G2, Canada.
authors.forename: Todd L
authors.initials: TL
authors.lastname: Lowary
authors.affiliation: Singapore Immunology Network, Agency for Science Technology and Research, Singapore 138648, Singapore.
authors.forename: Florent
authors.initials: F
authors.lastname: Ginhoux
authors.affiliation: Laboratory of Immunology, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Chae Gyu
authors.initials: CG
authors.lastname: Park
authors.affiliation: Institut de Researches Cliniques de Montréal, Montréal, Québec H2W1R7, Canada.
authors.forename: Cheolho
authors.initials: C
authors.lastname: Cheong
authors.affiliation: Department of Oncological Sciences Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Brody
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02284, USA.
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Turley
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.affiliation: Verona University Hospital, Verona 37129, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 2JD, England.
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Heeger
authors.affiliation: Department of Oncological Sciences Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.affiliation: Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany.
authors.forename: James
authors.initials: J
authors.lastname: Hutchinson
authors.affiliation: Department of Oncological Sciences Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Shu-Hsia
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA; Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid 28220, Spain. Electronic address: jordi.ochando@mssm.edu.
authors.forename: Jordi
authors.initials: J
authors.lastname: Ochando
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D016027:Heart Transplantation; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D023001:Transplantation Tolerance; D015854:Up-Regulation; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D051858:Forkhead Transcription Factors; D016753:Interleukin-10; D037181:Lectins, C-Type; D016173:Macrophage Colony-Stimulating Factor; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C498833:Foxp3 protein, mouse