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Immunity. 2015 Jun 16;42(6):1143-58. doi: 10.1016/j.immuni.2015.05.009. Epub 2015 Jun 9.

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

Author information

1
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
2
Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid 28220, Spain.
3
Department of Oncological Sciences Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
4
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
5
Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
6
Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
7
Institut de Researches Cliniques de Montréal, Montréal, Québec H2W1R7, Canada.
8
Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany.
9
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain.
10
Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
11
Laboratory of Immune Regulation, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.
12
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
13
Alberta Glycomics Centre and Department of Chemistry, University of Alberta, Edmonton T6G 2G2, Canada.
14
Singapore Immunology Network, Agency for Science Technology and Research, Singapore 138648, Singapore.
15
Laboratory of Immunology, Yonsei University College of Medicine, Seoul 120-752, Korea.
16
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02284, USA.
17
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
18
Verona University Hospital, Verona 37129, Italy.
19
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 2JD, England.
20
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.

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.

PMID:
26070485
PMCID:
PMC4690204
DOI:
10.1016/j.immuni.2015.05.009
[Indexed for MEDLINE]
Free PMC Article

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