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 GinhouxChae Gyu Park, Cheolho Cheong, Joshua Brody, Shannon J. Turley, Sergio A. Lira, Vincenzo Bronte, Siamon Gordon, Peter S. Heeger, Miriam Merad, James Hutchinson, Shu Hsia Chen, Jordi Ochando

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

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+ Tcell 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 invivo, 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.

Original languageEnglish (US)
Pages (from-to)1143-1158
Number of pages16
JournalImmunity
Volume42
Issue number6
DOIs
StatePublished - Jun 16 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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