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

134 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 (US)
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 - Jun 16 2015

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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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

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

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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",

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

language = "English (US)",

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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

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.

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DC-SIGN⁺ Macrophages Control the Induction of Transplantation Tolerance

Abstract

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