Indoleamine 2,3-Dioxygenase-Expressing Aortic Plasmacytoid Dendritic Cells Protect against Atherosclerosis by Induction of Regulatory T Cells

Tae Jin Yun, Jun Seong Lee, Kawthar Machmach, Dahee Shim, Junhee Choi, Young Jin Wi, Hyung Seok Jang, In Hyuk Jung, Kyeongdae Kim, Won Kee Yoon, Mohammad Alam Miah, Bin Li, Jinsam Chang, Mariana G. Bego, Tram N.Q. Pham, Jakob Loschko, Jörg Hermann Fritz, Anne B. Krug, Seung Pyo Lee, Tibor KelerJean V. Guimond, Elie Haddad, Eric A. Cohen, Martin G. Sirois, Ismail El-Hamamsy, Marco Colonna, Goo Taeg Oh, Jae Hoon Choi, Cheolho Cheong

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

Plasmacytoid dendritic cells (pDCs) are unique bone-marrow-derived cells that produce large amounts of type I interferon in response to microbial stimulation. Furthermore, pDCs also promote T cell tolerance in sterile-inflammation conditions. However, the immunomodulatory role of aortic pDCs in atherosclerosis has been poorly understood. Here, we identified functional mouse and human pDCs in the aortic intima and showed that selective, inducible pDC depletion in mice exacerbates atherosclerosis. Aortic pDCs expressed CCR9 and indoleamine 2,3-dioxygenase 1 (IDO-1), an enzyme involved in driving the generation of regulatory T cells (Tregs). As a consequence, loss of pDCs resulted in decreased numbers of Tregs and reduced IL-10 levels in the aorta. Moreover, antigen presentation by pDCs expanded antigen-specific Tregs in the atherosclerotic aorta. Notably, Tregs ablation affected pDC homeostasis in diseased aorta. Accordingly, pDCs in human atherosclerotic aortas colocalized with Tregs. Collectively, we identified a mechanism of atheroprotection mediated by tolerogenic aortic pDCs.

Original languageEnglish
Pages (from-to)852-866
Number of pages15
JournalCell Metabolism
Volume23
Issue number5
DOIs
StatePublished - 10 May 2016

Bibliographical note

Funding Information:
This work is dedicated to the memory of Dr. Cheolho Cheong. We thank the excellent support provided by the IRCM animal facility. This work was supported by grants from the Canadian Foundation for Innovation (John R. Evans Leaders Fund) and the Canadian Institutes of Health Research (CIHR) (MOP 125933 and 133050 to C.C.; MOP 111226 to E.A.C.; and MOP 97943 to M.G.S); by Canadian HIV Cure Enterprise Team Grant HIG-133050 (to C.C., E.A.C., and E.H.); and by National Research Foundation of Korea (NRF) grants funded by the Korean government (the Ministry of Science, ICT and Future Planning [NRF-2013S1A2A2035348 and 2013M3A9D5072550 to J.-H.C.; and 2012R1A3A2026454, 2015M3A9B6029138, 2010-0020878, and 2010-0019866 to G.T.O.]). E.A.C. holds a Canada Research Chair in Human Retrovirology. C.C. is a recipient of a CIHR New Investigator Award and holds an SQHA-FRQS J1 Scholarship. T.K. is an employee and shareholder of Celldex Therapeutics. Except T.K., none of the authors have a financial interest related to this work.

Publisher Copyright:
© 2016 Elsevier Inc.

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