The Importance of Dendritic Cells in Maintaining Immune Tolerance Cindy Audiger, M. Jubayer Rahman, Tae Jin Yun, Kristin V. Tarbell and Sylvie Lesage This information is current as of October 1, 2021. J Immunol 2017; 198:2223-2231; ; doi: 10.4049/jimmunol.1601629 http://www.jimmunol.org/content/198/6/2223 Downloaded from References This article cites 166 articles, 73 of which you can access for free at: http://www.jimmunol.org/content/198/6/2223.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology The Importance of Dendritic Cells in Maintaining Immune Tolerance x { Cindy Audiger,*,†,1 M. Jubayer Rahman,‡,1 Tae Jin Yun, , Kristin V. Tarbell,‡ and Sylvie Lesage*,† Immune tolerance is necessary to prevent the immune specific depletion of CD11c+ cells (3). CD11c is an integrin system from reacting against self, and thus to avoid expressed at high levels by DCs and at much lower levels by the development of autoimmune diseases. In this review, many cellular subsets, namely neutrophils, macrophages, NK we discuss key findings that position dendritic cells cells, as well as activated monocytes and T cells. Selective + (DCs) as critical modulators of both thymic and periph- depletion of CD11c cells induces an increase in effector Th1 eral immune tolerance. Although DCs are important for and Th17 cells and strong autoimmune symptoms, such as lymphadenopathy, splenomegaly, and infiltration of non- inducing both immunity and tolerance, increased auto- Downloaded from immunity associated with decreased DCs suggests their lymphoid organs (3–5). Elimination of DCs in mice thus is nonredundant role in tolerance induction. DC-mediated sufficient to break immune tolerance and lead to autoimmune T cell immune tolerance is an active process that is influ- pathology, suggesting that DCs play a central role in the enced by genetic variants, environmental signals, as well maintenance of immune tolerance. Notably, these findings were recently confirmed in a model that permits more selec- as the nature of the specific DC subset presenting Ag to tive elimination of DCs. Indeed, within the hematopoietic http://www.jimmunol.org/ T cells. Answering the many open questions with regard system, the Zbtb46 transcription factor is exclusively expressed to the role of DCs in immune tolerance could lead to the in DCs (6). The specific depletion of DCs in Zbtb46–diph- development of novel therapies for the prevention of au- theria toxin receptor (DTR) adult mice via diphtheria toxin toimmune diseases. The Journal of Immunology, 2017, injection causes lymphoangiogenesis and myeloproliferative 198: 2223–2231. disorders, thus confirming the importance of DCs in the maintenance of immune tolerance (7, 8). Interestingly, the ntigen-presenting cells, namely B cells, macrophages, autoimmune pathology was less severe in the Zbtb46-DTR and dendritic cells (DCs), initiate both protective mice when compared with the CD11c-DTA mice, possibly A and autoimmune T cell responses, and DCs bear the because of either the more selective nature of the Zbtb46-DTR by guest on October 1, 2021 highest Ag presentation potential, as shown by stronger in- model or the timing of DC deletion. The CD11c-DTA model duction of naive T cell activation (1). DCs play a nonre- continuously deletes DCs from early development, but the dundant role in the initiation of immune responses and the deletion of DCs in Zbtb46-DTR mice is transiently in- control of some pathogens. For instance, IRF8 mutations in duced in adult mice. Nevertheless, both experimental set- humans cause defects in DCs, resulting in opportunistic in- tings show that elimination of DCs in mice is sufficient to fections and an increase in anergic T cells (2). Additionally, break immune tolerance and lead to autoimmune pathology, DCs also play a key role in maintaining immune tolerance, as suggesting that DCs play a central role in the maintenance of we discuss in this review. immune tolerance. The importance of DCs in maintaining immune tolerance If depletion of DCs leads to autoimmune phenotypes, one was shown by using mouse models to manipulate the number could postulate that increasing the prevalence of DCs would of DCs in vivo. For one, the CD11c–Cre/ROSA-diphtheria strengthen immune tolerance and prevent autoimmune disease toxin A (CD11c-DTA) transgenic mouse model allows for occurrence. To this effect, Flt3 ligand injection increases the *Department of Immunology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Que´bec and by Fondation Lucie-Besner. S.L. is supported by Fonds de Recherche en Quebec H1T 2M4, Canada; †De´partement de Microbiologie, Infectiologie et Immu- Sante´ du Que´bec, and by grants from the Natural Sciences and Engineering Research nologie, Universite´ de Montre´al, Montreal, Quebec H3C 3J7, Canada; ‡Immune Tol- Council and the Cancer Research Society. erance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of T.J.Y. prepared the figures; C.A., M.J.R., K.V.T., and S.L. wrote the paper; all authors Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, x read and approved the manuscript. MD 20892; Laboratory of Cellular Physiology and Immunology, Clinical Research { Institute of Montreal, Montreal, Quebec H2W 1R7, Canada; and Division of Exper- Address correspondence and reprint requests to Dr. Sylvie Lesage, Research Center, imental Medicine, Department of Medicine, McGill University, Montreal, Quebec H3A Maisonneuve-Rosemont Hospital, 5415 l’Assomption Boulevard, Montreal, QC H1T 1A3, Canada 2M4, Canada. E-mail address: [email protected] 1C.A. and M.J.R. contributed equally to this work. Abbreviations used in this article: cDC, conventional DC; CD11c-DTA, CD11c–Cre/ ROSA-diphtheria toxin A; DC, dendritic cell; DTR, diphtheria toxin receptor; EAE, ORCIDs: 0000-0001-9087-9036 (C.A.); 0000-0002-0968-2795 (S.L.). experimental autoimmune encephalitis; GVHD, graft-versus-host disease; MHC-I, Received for publication September 19, 2016. Accepted for publication December 11, MHC class I; MHC-II, MHC class II; pDC, plasmacytoid DC; RTOC, reaggregate 2016. thymus organ culture; tol-DC, DC with tolerogenic properties; Treg, regulatory T cell. M.J.R. and K.V.T. are supported by the intramural research programs of the National Ó Institute of Diabetes and Digestive and Kidney Diseases. C.A. is supported by a schol- Copyright 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 arship from the Montreal Diabetes Research Center in collaboration with Diabe`te www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601629 2224 BRIEF REVIEWS: DENDRITIC CELLS IN IMMUNE TOLERANCE proportion of DCs in vivo and prevents autoimmune diabetes ofsuperantigens,toinduceeffectivecentraltolerance(27). onset in NOD mice (9). However, a break in immune tol- In comparison with macrophages and B cells, only DCs were erance is observed in mouse models where DC number is able to induce negative selection of thymocytes in reaggre- increased by inhibiting DC apoptosis. Specifically, transgenic gate thymus organ cultures (RTOCs) (25), showing the dom- mice with CD11c promoter-driven p35, a caspase inhibi- inant role of DCs in central tolerance. More recently, it was tor that blocks apoptosis, present with an accumulation shown that DCs are not simply bystanders in the thymocyte of DCs in lymphoid organs over time (10). Consequently, selection process. They actively attract postpositive selection CD11c-p35 transgenic mice exhibit lymphocytic infiltration thymocytes by producing CCR4 ligand to facilitate the neg- in nonlymphoid organs, activation of both T and B cells, and ative selection process (28). Interestingly, and likely due to the production of anti-DNA Ab (10). Also, DC-specific knock- experimental challenges associated with separating central and out of Bim decreases DC apoptosis, which leads to an increase peripheral tolerance processes, the general outcome of a defect in DCs and results in inflammation (11). Therefore, depending in DC-mediated central tolerance on the potential develop- on the context, an increase in the number of DCs can either ment of an autoimmune phenotype has yet to be clearly de- increase or decrease T cell tolerance. This is perhaps due to fined. distinct impacts on the DC phenotype, such that expansion of Although all thymic DCs contribute to central tolerance, DCs either by stimulating hematopoiesis or by blocking DC they do so through different means (Fig. 1). Three thymic DC apoptosis may yield different outcomes in the maintenance subsets contribute to central tolerance, namely resident DCs 2 2 of immune tolerance. Still, because DCs are capable