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; Shu Hsia Chen; Jordi Ochando

doi:10.1016/j.immuni.2015.05.009

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 journal › Article › peer-review

126 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 language	English
Pages (from-to)	1143-1158
Number of pages	16
Journal	Immunity
Volume	42
Issue number	6
DOIs	https://doi.org/10.1016/j.immuni.2015.05.009
State	Published - 16 Jun 2015

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10.1016/j.immuni.2015.05.009

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Conde, P., Rodriguez, M., van der Touw, W., Jimenez, A., Burns, M., Miller, J., Brahmachary, M., Chen, H. M., Boros, P., Rausell-Palamos, F., Yun, T. J., Riquelme, P., Rastrojo, A., Aguado, B., Stein-Streilein, J., Tanaka, M., Zhou, L., Zhang, J., Lowary, T. L., ... Ochando, J. (2015). DC-SIGN⁺ Macrophages Control the Induction of Transplantation Tolerance. Immunity, 42(6), 1143-1158. https://doi.org/10.1016/j.immuni.2015.05.009

@article{93ba36423b234b7788e94041f70f2b27,

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+ 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.",

author = "Patricia Conde and Mercedes Rodriguez and {van der Touw}, William and Ana Jimenez and Matthew Burns and Jennifer Miller and Manisha Brahmachary and Chen, {Hui ming} and Peter Boros and Francisco Rausell-Palamos and Yun, {Tae Jin} and Paloma Riquelme and Alberto Rastrojo and Bego{\~n}a Aguado and Joan Stein-Streilein and Masato Tanaka and Lan Zhou and Junfeng Zhang and Lowary, {Todd L.} and Florent Ginhoux and Park, {Chae Gyu} and Cheolho Cheong and Joshua Brody and Turley, {Shannon J.} and Lira, {Sergio A.} and Vincenzo Bronte and Siamon Gordon and Heeger, {Peter S.} and Miriam Merad and James Hutchinson and Chen, {Shu Hsia} and Jordi Ochando",

note = "Funding Information: We thank Andres Hidalgo (Centro Nacional de Investigaciones Cardiovasculares, ISCIII) and Emmanuel Gautier (Department of Pathology & Immunology, Washington University) for critical review of the manuscript. We acknowledge the technical contributions of the Flow Cytometry, Microsurgery, and the Biorepository/Pathology Centers of Research Excellence at Mount Sinai, and the Alberta Glycomics Centre for their help on the LNFPIII synthesis. Acknowledgments to Marcy Kuentzel and Sridar Chittur at the University of Albany Center for Functional Genomics Microarray Core facility for their assistance in generating the microarray data. This work was supported by the COST Action BM1305: Action to Focus and Accelerate Cell Tolerogenic Therapies (A FACTT), the Mount Sinai Recanati/Miller Transplantation Institute developmental funds, AST/Pfizer Basic Science Faculty Development Grant, Ministerio de Educaci{\'o}n y Ciencia SAF2010-15062, SAF2013-48834-R, and Fundaci{\'o}n Mutua Madrile{\~n}a grants to J.O. A portion of this work appears as part of the doctoral thesis of P.C. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = jun,

day = "16",

doi = "10.1016/j.immuni.2015.05.009",

language = "English",

volume = "42",

pages = "1143--1158",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "6",

}

Conde, P, Rodriguez, M, van der Touw, W, Jimenez, A, Burns, M, Miller, J, Brahmachary, M, Chen, HM, Boros, P, Rausell-Palamos, F, Yun, TJ, Riquelme, P, Rastrojo, A, Aguado, B, Stein-Streilein, J, Tanaka, M, Zhou, L, Zhang, J, Lowary, TL, Ginhoux, F, Park, CG, Cheong, C, Brody, J, Turley, SJ, Lira, SA, Bronte, V, Gordon, S, Heeger, PS, Merad, M, Hutchinson, J, Chen, SH & Ochando, J 2015, 'DC-SIGN⁺ Macrophages Control the Induction of Transplantation Tolerance', Immunity, vol. 42, no. 6, pp. 1143-1158. https://doi.org/10.1016/j.immuni.2015.05.009

TY - JOUR

T1 - DC-SIGN+ Macrophages Control the Induction of Transplantation Tolerance

AU - Conde, Patricia

AU - Rodriguez, Mercedes

AU - van der Touw, William

AU - Jimenez, Ana

AU - Burns, Matthew

AU - Miller, Jennifer

AU - Brahmachary, Manisha

AU - Chen, Hui ming

AU - Boros, Peter

AU - Rausell-Palamos, Francisco

AU - Yun, Tae Jin

AU - Riquelme, Paloma

AU - Rastrojo, Alberto

AU - Aguado, Begoña

AU - Stein-Streilein, Joan

AU - Tanaka, Masato

AU - Zhou, Lan

AU - Zhang, Junfeng

AU - Lowary, Todd L.

AU - Ginhoux, Florent

AU - Park, Chae Gyu

AU - Cheong, Cheolho

AU - Brody, Joshua

AU - Turley, Shannon J.

AU - Lira, Sergio A.

AU - Bronte, Vincenzo

AU - Gordon, Siamon

AU - Heeger, Peter S.

AU - Merad, Miriam

AU - Hutchinson, James

AU - Chen, Shu Hsia

AU - Ochando, Jordi

N1 - Funding Information: We thank Andres Hidalgo (Centro Nacional de Investigaciones Cardiovasculares, ISCIII) and Emmanuel Gautier (Department of Pathology & Immunology, Washington University) for critical review of the manuscript. We acknowledge the technical contributions of the Flow Cytometry, Microsurgery, and the Biorepository/Pathology Centers of Research Excellence at Mount Sinai, and the Alberta Glycomics Centre for their help on the LNFPIII synthesis. Acknowledgments to Marcy Kuentzel and Sridar Chittur at the University of Albany Center for Functional Genomics Microarray Core facility for their assistance in generating the microarray data. This work was supported by the COST Action BM1305: Action to Focus and Accelerate Cell Tolerogenic Therapies (A FACTT), the Mount Sinai Recanati/Miller Transplantation Institute developmental funds, AST/Pfizer Basic Science Faculty Development Grant, Ministerio de Educación y Ciencia SAF2010-15062, SAF2013-48834-R, and Fundación Mutua Madrileña grants to J.O. A portion of this work appears as part of the doctoral thesis of P.C. Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/6/16

Y1 - 2015/6/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84937551237&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2015.05.009

DO - 10.1016/j.immuni.2015.05.009

M3 - Article

C2 - 26070485

AN - SCOPUS:84937551237

SN - 1074-7613

VL - 42

SP - 1143

EP - 1158

JO - Immunity

JF - Immunity

IS - 6

ER -

DC-SIGN+ Macrophages Control the Induction of Transplantation Tolerance

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DC-SIGN⁺ Macrophages Control the Induction of Transplantation Tolerance