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Parasites Leishmania Modulation of Dendritic Cell Function By Modulation of Dendritic Cell Function by Leishmania Parasites Lynn Soong This information is current as J Immunol 2008; 180:4355-4360; ; of September 28, 2021. doi: 10.4049/jimmunol.180.7.4355 http://www.jimmunol.org/content/180/7/4355 Downloaded from References This article cites 68 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/180/7/4355.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 September 28, 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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY BRIEF REVIEWS Modulation of Dendritic Cell Function by Leishmania Parasites1 Lynn Soong2 The interactions between Leishmania parasites and den- form that replicates within the acidified parasitophorous vacu- dritic cells (DCs) are complex and involve paradoxical oles (1). The promastigotes interact with mammalian hosts very functions that can stimulate or halt T cell responses, lead- briefly without causing clinical manifestations, whereas amasti- ing to the control of infection or progression of disease. The gotes persist in their hosts for years or for a lifetime and are magnitude and profile of DC activation vary greatly, de- hence responsible for clinical diseases. Those working in this pending upon the Leishmania species/strains, develop- field have focused on gaining a better understanding of the pro- mental stages, DC subsets, serum opsonization, and exog- cesses by which the promastigotes establish the infection and Downloaded from enous DC stimuli involved in the study. In general, the the amastigotes modulate or take advantage of their host’s im- uptake of Leishmania parasites alone can trigger rela- mune system. However, investigation into the molecular details tively weak and transient DC activation; however, the in- of the means by which the host cell interacts with amastigotes tracellular parasites (amastigotes) are capable of down- has been partially hampered by the limited availability of amas- modulating LPS/IFN-␥-stimulated DC activation via tigotes for some Leishmania species. Although axenically cul- http://www.jimmunol.org/ multiple mechanisms. This review will highlight current tured amastigotes are readily available for some species (e.g., data regarding the initial interaction of DC subsets with Leishmania amazonensis and Leishmania mexicana), other amas- invading parasites, the alterations of DC signaling path- tigote species need to be freshly prepared from mouse/hamster ways and function by amastigotes, and the impact of lesions or generated from cultured promastigotes (via reduction of culture pH and increase of temperature). DC functions on protective immunity and disease Another challenge in defining the molecular details of the pathogenesis. Available information provides insight host-Leishmania interaction is the complex regulation of spe- into the mechanisms by which DCs discriminate be- cies- and stage-specific genes. The Leishmania genome is spread tween the types of pathogens and regulate appropriate over 34ϳ36 chromosome pairs containing ϳ8,160 genes. by guest on September 28, 2021 immune responses. The Journal of Immunology, Global analyses of gene expression indicate that the vast major- 2008, 180: 4355–4360. ity (Ͼ95%) of genes are constitutively expressed in all life stages and that for the few dozen of the amastigote-specific genes iden- eishmaniasis is a vector-transmitted disease distributed tified, they are relatively specific for a given Leishmania species throughout the world’s tropical and subtropical re- (2). Therefore, information learned from one Leishmania spe- L gions. At least 20 Leishmania species can give rise to a cies may not be applicable to other species. For example, there is wide spectrum of clinical manifestations, ranging from self- a great need for comparative studies of Leishmania major and healing skin ulcers to disfiguring mucosal lesions and fatal vis- Leishmania donovani (etiological agents of the Old World cu- ceral infections. Although the determinants of parasite tissue taneous and visceral leishmaniasis, respectively), as well as of L. tropism remain unclear, the diverse clinical forms are believed amazonensis and Leishmania braziliensis (etiological agents of to be attributable to the host immune status and the species of diffuse cutaneous and mucosal leishmaniasis in South America, parasite involved. Leishmania parasites have a dimorphic life cy- respectively). In this regard, animal studies have clearly indi- cle. Initially, the infectious promastigote form of the parasite is cated that L. major can cause a Th2-mediated, lethal infection transmitted to the mammalian host by the bite of sand flies. in BALB/c mice but a Th1-mediated, self-healing infection in Once phagocytosed by cells in the macrophage (M⌽)3 lineage, C57BL/6 and C3H mice, whereas L. amazonensis often causes the promastigotes differentiate into a nonmotile amastigote progressive, nonhealing lesions in all of these mouse strains (3) Departments of Microbiology & Immunology and Pathology, Center for Biodefense and ing 3.142, 301 University Boulevard, Galveston, TX 77555-1070. E-mail address: Emerging Infectious Diseases, Sealy Center for Vaccine Development, Institute for Hu- [email protected] man Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555 3 Abbreviations used in this paper: M⌽, macrophage; DC, dendritic cell; DC-SIGN, den- Received for publication September 11, 2007. Accepted for publication January 31, 2008. dritic cell-specific ICAM-3-grabbing nonintegrin; LC, Langerhans cell; LN, lymph node; LPG, lipophosphoglycan; mDC, myeloid DC; pDC, plasmacytoid DC; PMN, polymor- The costs of publication of this article were defrayed in part by the payment of page charges. phonuclear neutrophil. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 1 This work was supported by National Institutes of Health Grants AI043003 and AI039540). 2 Address correspondence and reprint requests to Dr. Lynn Soong, Department of Micro- biology and Immunology, University of Texas Medical Branch, Medical Research Build- www.jimmunol.org 4356 BRIEF REVIEWS: MODULATING DC FUNCTION BY LEISHMANIA PARASITES due to an IL-4/IL-10-independent impairment in innate and acquired immunity (4, 5). This review will highlight available evidence at the DC level that may explain the diverse outcomes of Leishmania infection. M⌽s are the main host cells for Leishmania replication and the effector cell for parasite killing. Leishmania infection does not trigger inflammatory M⌽s to produce IL-12 (6), and par- ϩ asite-carrying M⌽s are incompetent in priming naive CD4 T ϩ cells or stimulating Ag-specific CD4 T cells (7). The molecu- lar details have been reviewed elsewhere with respect to how promastigotes and amastigotes bind to M⌽ surface receptors and interfere with their effector functions (8, 9). The recent ad- FIGURE 1. A schematic view of the hierarchy within different cell types, vancements in the biology of DC subsets, as well as in the re- receptors, and cytokines in activating innate and adaptive immunity at the ini- tial stages of infection with Leishmania promastigotes. Following the initial in- agents used, have greatly enhanced our understanding of DC- fection with Leishmania promastigotes, PMNs are recruited within hours to the Leishmania interactions, and several reviews have summarized site of infection and constitute the majority of the cellular infiltrates in the first the critical role of myeloid DCs (mDCs) in generating protec- day of infection. Parasite infection in PMNs may trigger the expression of tive immunity against L. major infection (10–12). New data TLR2, 7, and 9, as well as the production of some IL-12. Although pDCs do also call for re-evaluation of the accepted paradigm in L. major not endocytose promastigotes, they can be activated via released Leishmania Downloaded from ␣␤ infection (13, 14). This review will focus on recent data related genomic DNA (gDNA) to produce appreciable amounts of IFN- and some IL-12 in a TLR9-dependent manner. mDCs and monocyte-derived DCs can to the initial interactions of DC subsets with promastigote in- efficiently engulf promastigotes, serving as a critical source of early IL-12 pro- fection in vivo, alterations of DC signaling pathways by amas- duction. Activated DCs can migrate to draining LNs, activate resting NK cells tigotes, the impact of these alterations on disease outcomes, and via cell contact-dependent manner, and trigger NK cells to produce IFN-␥. The the potential of DC-based vaccines in animal models of cuta- cognate interactions among multiple
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