Parasites Leishmania Modulation of Dendritic Cell Function By

Home , Leishmania donovani

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 molecular 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 initial 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 innate cell types and cytokines at the site neous leishmaniasis. Emphasis will be placed on DC responses of infection and in draining LNs are required for appropriate activation of pro- http://www.jimmunol.org/ to the species of amastigotes in the L. mexicana complex, espe- tective Th1 responses against the invading pathogens. However, the magnitude cially to L. amazonensis because of its association with profound of DC and Th1 cell activation in vivo varies greatly, depending upon the species of parasites involved. T cell suppression in patients with diffuse cutaneous leishmaniasis (15, 16) and its ability to cause nonhealing skin lesions in several inbred mouse strains that are genetically resistant to L. major parasites. For some time the nature and specific functions of migratory DCs in cutaneous leishmaniasis have been matters of contro- The interaction of DC subsets with Leishmania promastigotes in vivo high versy. Although both dermal DC immigrants (MHC II , by guest on September 28, 2021 ϩ ϩ Ϫ Because leishmaniasis is initiated by promastigote infection in CD11c , CD11b , CD8␣ , and CD205low) and epidermal ϩ the skin, extensive studies have been conducted in mouse mod- Langerhans cells (LCs) (MHC IIhigh, CD11c , CD11blow, ϩ els of L. major infection to define the early source of IL-12 and CD8ainter, CD205high, and Langerin ) can home to the drain- the role of different DC subsets in infection. Most of the re- ing lymph nodes (LNs), they may have different capacities in ported studies, however, have used supraphysiologic doses of engulfing promastigotes and distinct functions in experimental promastigotes in the absence of sand fly influence, which is leishmaniasis (13, 26). In L. major infection, parasite Ags are known to modulate DC maturation/activation (17) and local believed to be transported from the site of infection to draining ϩ Ϫ Ϫ immune responses (18). Following skin injection of L. major LNs by CD11c CD8␣ Langerin dermal DCs rather than by promastigotes, polymorphonuclear neutrophils (PMN) are re- LCs (27) because LCs are less efficient in the uptake of promas- cruited to the infection site within hours and constitute the ma- tigotes. These recent data challenge our previous view on LCs jority of cellular infiltrates within the first day of infection (19). (28) and support the hypothesis that dermal DCs carry parasite Although L. major-infected PMNs could constitute one of the Ag to activate Th1 effector cells, whereas epidermal LCs take up earliest sources of IL-12 in resistant C57BL/6 mice, possibly via free Ag released from parasites or damaged host cells to activate the activation of TLR2, 7, and 9 (20), some parasite-carrying other T cell subsets (13). More recent data from L. major-in- PMNs can act as “Trojan horses” to transfer parasites to M⌽s, fected tissues and adoptive transfer of purified monocytes have promoting TGF-␤ production by M⌽s and establishing the in- provided new evidence, indicating the importance of the kinet- fection in M⌽s (21, 22). The means by which these early events influence DC recruitment and activation remain unclear. Sev- ics of cellular recruitment during infection and the de novo dif- eral DC subsets are involved in Leishmania infection. Plasma- ferentiation of monocytes to DCs, as well as the role of this DC cytoid DCs (pDCs) can be detected in the infected skin; how- subset in inducing parasite-specific Th1 responses in the drain- ever, they may not endocytose Leishmania promastigotes but ing LNs (14). Collectively, these in vivo studies suggest the dy- can be activated by released Leishmania genomic DNA to pro- namics of the DC network during infection-induced inflamma- duce appreciable amounts of IFN-␣␤ and some IL-12 in a tory reactions and the importance of fully activated mDCs high high ϩ ϩ TLR9-dependent manner (23). Although adoptively trans- (CD86 , CD40 , CCR7 , and IL-12 ) in TLR-9-medi- ferred pDCs contribute to the control of L. major infection in ated activation of NK cells and in the generation of protective mice (24), in vivo studies suggest that mDCs and IL-12, rather Th1 responses against Leishmania parasites (Fig. 1). At present, than pDCs and IFN-␣␤, are required for NK cell cytotoxicity there is still limited information on initial DC responses to and IFN-␥ production in cutaneous and visceral leishmaniasis other species of Leishmania at the site of infection and on the (23, 25). priming of pathogenic T cells. The Journal of Immunology 4357

comparison to other pathogens that have chemically defined ligands for multiple TLRs (39), TLR ligand involvement is less clear for Leishmania parasites. Although circumstantial evidence suggests the involvement of LPG as well as TLR2, 3, 4, 7, and 9, in Leishmania infection (20, 40–42), the lack of strong TLR ligands in Leishmania infection may partially explain the relatively weak DC activation induced by promastigote infec- FIGURE 2. Transient expression of the IL-12p40 gene in DCs following tion alone. infection with L. amazonensis promastigotes. Bone marrow-derived C57BL/6 DCs were infected with promastigotes (red lines) and amastigotes (blue lines) Down-modulation of DC functions by Leishmania amastigotes for 8 and 24 h, respectively. To examine the effect of parasitic infection on DC The molecular details of how DCs deal with the disease-form- responsiveness to other stimuli, cells were infected with parasites for6hand then treated with IFN-␥ (100 ng/ml) plus LPS (100 ng/ml) for an additional 2 ing amastigotes are still convoluted. In contrast to promastig- or 18 h, respectively. LPS/IFN-␥-treated DCs are denoted by a dashed line. The otes, Leishmania amastigotes are largely deficient in LPG and levels of IL-12p40 mRNA were quantified by real-time RT-PCR (normalized have several unique biological features (9). First, the avidity of to the ␤-actin gene) and are presented as relative expression fold in comparison Leishmania for the surface C-type lectin called DC-specific to those of untreated DCs. ICAM-3-grabbing nonintegrin (DC-SIGN or CD209) and DC-SIGN-related molecules varies greatly with the parasite species and maturation stage in question. For example, amasti- Downloaded from DC responsiveness to Leishmania promastigote infection in vitro gotes of L. amazonensis, L. mexicana, L. donovani, but not L. To define the means by which DCs respond to Leishmania par- major, can bind to DC-SIGN (43, 44). Because this binding is ϩ asites and Ag-specific CD4 T cells are activated, extensive independent of LPG and does not induce DC maturation (44), studies have been performed with bone marrow-derived mouse the benefits of engaging to DC-SIGN in these DCs remain mDCs, skin-derived mouse LCs, or monocyte-derived human enigmatic (45). Second, lesion-derived amastigotes are com- DCs. In vitro infection studies have collectively indicated that monly coated with host Abs. Whereas Ab opsonization pro- http://www.jimmunol.org/ mDCs (but not LCs) can efficiently engulf promastigotes, and motes the uptake of L. major amastigotes by murine mDCs and that infection with parasites in the absence of other stimuli can skin-derived LCs (6, 46), amastigotes of L. amazonensis (47), L. activate DCs to produce little IL-12p70 but a range of IL- mexicana (48), and L. braziliensis (D. A. Vargas-Inchaustegui, 12p40 and IL-10 (29–31). Nevertheless, IL-12p40 and IL- L. Xin, and L.Soong, submitted for publication) are highly ef- 12p70 production by infected DCs can be markedly enhanced ficient in infecting mDCs, even in the absence of any Abs. Nev- by the addition of exogenous stimuli (e.g., IL-1, IFN-␥, IFN- ertheless, Ab opsonization of amastigotes (and promastigotes) ␥/LPS, CD40L, and anti-CD40) at the time of infection (29, significantly enhances DC activation and the production of

31, 32). Promastigote-infected, IL-12p40-producing mDCs IL-10 (and IL-12p40, to some extent) (6, 47) via the Fc␥R- by guest on September 28, 2021 Ϫ ϩ ϩ have a CD11chighCD45BR CD83 CD40 phenotype (31). mediated pathway (49). Consequently, such DCs preferentially ϩ Although infection with L. donovani and L. major promastig- prime IL-10-producing CD4 T cells and promote lesion pro- otes can trigger the release of preformed IL-12p70 and the progression in mice (47, 48). In contrast, other studies have shown duction of IL-12p40 (6, 33), the up-regulation of the IL-12p40 that the uptake of Ab-opsonized L. major amastigotes by mu- gene in L. amazonensis-infected mDCs appears to be relatively rine mDCs or lesion-derived L. donovani amastigotes by human weak and transient (31) (L. Xin, K. Li, and L. Soong, submitted mDCs activates DCs to produce IL-12 and to induce protective for publication). Although there was an ϳ16- and 1300-fold immunity (46, 50). In further contrast, uptake of opsonized L. induction in IL-12p40 gene expression at8hofinfection in the major amastigotes by BALB/c mDCs preferentially stimulates absence or presence of LPS/IFN-␥, respectively, the expression the production of IL-12p40 and the formation of inhibitory levels dropped dramatically by 24 h postinfection (Fig. 2). De- IL-12p40 homodimers (51). The differences in DC cytokine pending on the species of the parasites involved, promastigote profiles may partially explain the complex roles of Ab in leish- infection was able to marginally or partially reduce DC respon- maniasis (12, 47, 52). siveness to exogenous stimuli (29, 31) and to impair DC differ- Although L. amazonensis amastigotes can infect Ͼ80% of ϩ entiation in vitro (34). CD11c mDCs in Ͻ30 min, they are especially poor at acti- The responsiveness of mDCs to different Leishmania pro- vating these cells (35, 48). Live L. amazonensis amastigotes also mastigotes can be roughly ranked in the order of L. major and L. markedly alter DC responsiveness to exogenous stimuli braziliensis Ͼ L. donovani and Leishmania infantum Ͼ L. mexi- (IFN-␥, LPS, and LPS/IFN-␥), and amastigote-infected DCs ϩ cana and L. amazonensis as judged by the expression levels of are poor APCs in priming naive CD4 T cells in vitro and in surface markers and cytokines and APC potential in priming vivo (35) (L. Xin, J. Li, and L. Soong, submitted for publica- ϩ naive CD4 T cells (31, 32, 35) (D. A. Vargas-Inchaustegui, L. tion). Although IL-10 can be readily detected in amastigote- Xin, and L. Soong, submitted for publication). It is well known infected mDCs (30), current evidence suggests that the down- that promastigote surface molecules, such as lipophosphogly- modulation of DC activation following amastigote infection is can (LPG), can suppress M⌽ functions (36); however, LPG, not due to endogenous IL-10 but rather to reduced phosphor- but not the lipid-free LPG, can also activate murine mDCs and ylation and/or accelerated degradation of key molecules in the NK cells through TLR2 (37). Given the marked multiplicity in JAK/STAT, NF-␬B, and IFN regulatory factor (IRF) pathways LPG glycan side chains (composition and position on the LPG via parasite-derived proteinases and oligopeptidases (Fig. 3). core structure) (38), it will be important to examine whether This hypothesis is supported by several lines of evidence. First, diverse DC responses to promastigotes are solely due to LPG heat inactivation (56oC for 30 min) or pretreatment of amasti- (32) or to other undefined pattern-recognition molecules. In gotes with protease inhibitors averts host protein degradation, 4358 BRIEF REVIEWS: MODULATING DC FUNCTION BY LEISHMANIA PARASITES

specific roles for IL-12 and IFN-␣) is observed in the case of pDC-immunized mice (24). These findings indicate the func- tional diversity of DC subsets in the control of L. major infection and the importance of mounting adequate local immune responses to control the infection (63). However, direct lesional injection of L. amazonensis Ag-pulsed mDCs (106 cells per mouse) together with rIL-12 failed to promote healing in mice chronically infected with L. amazonensis (35). Therefore, sim- ply providing in vitro-activated DCs or primed Th1 cells is not sufficient to ensure healing in L. amazonensis-infected hosts (35, 64). Additional treatments aimed at reducing intracellular FIGURE 3. Down-modulation of cytokine- and TLR4-mediated DC acti- parasite loads and/or blocking a parasite’s enzymatic activities vation and IL-12 production in DCs by Leishmania amastigotes. L. amazonensis are needed to outwit the parasites and thereby stem their amastigotes can efficiently enter mDCs, preventing and actively suppressing persistence. DC maturation/activation and IL-12 production. Alterations in amastigote-infected, LPS/IFN-stimulated DCs are mostly attributed to suppressed activation The development of DC-based immunotherapy for the con- and/or accelerated degradation of components in the JAK/STAT, NF-␬B, and trol of cutaneous leishmaniasis and other infectious diseases re- IFN regulator factor (IRF) pathways via parasite-derived proteinases and oli- quires a better understanding of the following: 1) the differ- gopeptidases rather than to the endogenous production of IL-10. Alterations in ences in the homing of transferred DCs to draining LNs and Downloaded from DC activation and function can result in an impaired activation of NK cells and into a particular T cell activation compartment (13); 2) the re- parasite-specific Th1 cells, leading to uncontrolled parasite replication and per- quirement for additional DC stimuli in vaccination protocols sistent infection. (63); and 3) the contribution of microenvironmental factors in DC functions during the early and late phases of infection (65). permitting DC activation to some extent (30)(L. Xin, K. Li, Given the unique features of DC-amastigote interaction, DC- and L. Soong, submitted for publication). Second, Leishmania based vaccination studies should be extended to those hosts http://www.jimmunol.org/ parasites are known to contain a vast repertoire of proteolytic having an established infection. Targeted delivery of leishma- enzymes encoding at least 154 peptidases (aspartic, cysteine, nial Ag to endogenous DCs (66) and the use of genetically en- metallo, serine, and threonine peptidases) (53), and amastigotes gineered parasites that express the DC activator (67) are other of L. amazonensis and L. mexicana are notorious for their high attractive approaches. cysteine protease/oligopeptidase B activities in specialized structures called megasomes (54, 55). The cathepsin B-like cysteine proteinase is central to the parasites’ ability to modulate Conclusions Leishmania parasites, especially their intracellular forms, have NF-␬B signaling and to consequently inhibit IL-12 production by guest on September 28, 2021 by murine M⌽s (56), and targeted depletion of its encoding evolved complex strategies to evade DC functions. While infec- gene greatly reduces parasite virulence (57). At present, it is un- tion with promastigotes alone can induce dermal DCs and clear how parasite components travel through the parasitopho- mDCs to mature, these activated DCs only transiently produce rous vacuole membrane to interfere with host signaling path- relatively low amounts of proinflammatory cytokines. In vitro ways and whether such down-modulation is specific to studies have suggested that promastigote-infected DCs retain their responsiveness to exogenous DC stimuli, producing ap- activation-related pathways. Nevertheless, alterations in DC ac- ␣ tivation/migration may be a general phenomenon in Leishma- preciable levels of IL-1, TNF- , IL-12p70, and IL-10, depend- nia infection, especially during the chronic stages (58, 59). ing upon the nature and combination of stimuli. Infection with Leishmania amastigotes, however, often fails to induce DC ac- DC-based immunotherapy in murine models of leishmaniasis tivation, presumably due to the general lack of LPG and the Examinations of the utility of DC vaccination as cellular im- direct effect of amastigote proteinases/oligopeptidases in host munotherapy for cancers have yielded some encouraging results cell signaling pathways. There is an increasing awareness of spe- and prompted similar studies in animal models of leishmania- cies- and strain-dependent differences in DC responsiveness to sis. Although DC-based vaccination may lack a conspicuous ap- Leishmania parasites. Likewise, marked differences are evident plication for parasitic diseases endemic in developing countries, in the biological roles of different DC subsets. The molecular it serves as a valuable tool for defining DC-targeted control basis of parasite-derived and DC-derived differences remains methods. Using L. major infection as a model, Moll and col- enigmatic, although DC-based studies have provided valuable leagues have shown that a single i.v. injection of ex vivo Ag- information. The details are largely unexplored with regard to pulsed LCs (60), mDCs (61), or pDCs (24) (5 ϫ 104 ϳ 5 ϫ how different DC subsets interact with promastigotes during 105 cells per mouse) is sufficient to induce protective immunity natural infection in vivo and with amastigotes, especially at the against single or repeated parasite challenges in susceptible chronic stages of infection. The availability of molecularly en- BALB/c mice. Interestingly, Ag-pulsed LCs and pDCs can me- gineered, traceable, and suicidal parasites (68, 69) would pro- diate protection independent of additional DC stimuli (CpG, vide additional tools to advance our understanding of host-par- TNF-␣, LPS, or CD40 ligation); however, overnight exposure asite interactions. to CpG motifs is required for Ag-loaded mDCs to induce specific Th1 responses (61), a phenomenon also observed for Acknowledgments mDCs pulsed with L. infantum Ag (62). In addition, while a I thank David Sacks and Mary Ann McDowell for insightful discussion and polarized Th1 cytokine profile is linked to protection in LC- critiques and additional thank Mardelle Susman for proofreading the and CpG/mDC-immunized mice, no strong correlation (or manuscript. The Journal of Immunology 4359

27. Ritter, U., A. Meissner, C. Scheidig, and H. Korner. 2004. CD8␣- and Langerin- Disclosures negative dendritic cells, but not Langerhans cells, act as principal antigen-presenting The authors have no financial conflict of interest. cells in leishmaniasis. Eur. J. Immunol. 34: 1542–1550. 28. Moll, H., H. Fuchs, C. Blank, and M. Rollinghoff. 1993. Langerhans cells transport Leishmania major from the infected skin to the draining lymph node for presentation References to antigen-specific T cells. Eur. J. Immunol. 23: 1595–1601. 1. McConville, M. J., D. d. Souza, E. Saunders, V. A. Likic, and T. Naderer. 2007. 29. von Stebut, E., Y. Belkaid, B. V. Nguyen, M. Cushing, D. L. Sacks, and M. C. Udey. Living in a phagolysosome; metabolism of Leishmania amastigotes. Trends Parasitol. 2000. Leishmania major-infected murine Langerhans cell-like dendritic cells from sus- 23: 368–375. ceptible mice release IL-12 after infection and vaccinate against experimental cutane- 2. Cohen-Freue, G., T. R. Holzer, J. D. Forney, and W. R. McMaster. 2007. Global ous leishmaniasis. Eur. J. Immunol. 30: 3498–3506. gene expression in Leishmania. Int. J. Parasitol. 37: 1077–1086. 30. Qi, H., V. Popov, and L. Soong. 2001. Leishmania amazonensis-dendritic cell inter- 3. McMahon-Pratt, D., and J. Alexander. 2004. Does the Leishmania major paradigm of ϩ pathogenesis and protection hold for New World cutaneous leishmaniases or the vis- actions in vitro and the priming of parasite-specific CD4 T cells in vivo. J. Immunol. 167: 4534–4542. ceral disease? Immunol. Rev. 201: 206–224. ␤ 4. Ji, J., J. Sun, and L. Soong. 2003. Impaired expression of inflammatory cytokines and 31. Xin, L., Y. Li, and L. Soong. 2007. The role of IL-1 in activating CD11chighCD45RBϪ DC subset and priming Leishmania amazonensis-specific chemokines at early stages of infection with Leishmania amazonensis. Infect. Immun. ϩ 71: 4278–4288. CD4 T cells in vitro and in vivo. Infect. Immun. 75: 5018–5026. 5. Jones, D. E., M. R. Ackermann, U. Wille, C. A. Hunter, and P. Scott. 2002. Early 32. McDowell, M. A., M. Marovich, R. Lira, M. Braun, and D. Sacks. 2002. Leishmania enhanced Th1 response after Leishmania amazonensis infection of C57BL/6 interleu- priming of human dendritic cells for CD40 ligand-induced interleukin-12p70 secre- kin-10-deficient mice does not lead to resolution of infection. Infect. Immun. 70: tion is strain and species dependent. Infect. Immun. 70: 3994–4001. 2151–2158. 33. Quinones, M., S. K. Ahuja, P. C. Melby, L. Pate, R. L. Reddick, and S. S. Ahuja. 6. von Stebut, E., Y. Belkaid, T. Jakob, D. L. Sacks, and M. C. Udey. 1998. Uptake of 2000. Preformed membrane-associated stores of interleukin (IL)-12 are a previously Leishmania major amastigotes results in activation and interleukin 12 release from mu- unrecognized source of bioactive IL-12 that is mobilized within minutes of contact rine skin-derived dendritic cells: implications for the initiation of anti-Leishmania im- with an intracellular parasite. J. Exp. Med. 192: 507–516. munity. J. Exp. Med. 188: 1547–1552. 34. Favali, C., N. Tavares, J. Clarencio, A. Barral, M. Barral-Netto, and C. Brodskyn.

7. Kima, P. E., L. Soong, C. Chicharro, N. H. Ruddle, and D. McMahon-Pratt. 1996. 2007. Leishmania amazonensis infection impairs differentiation and function of hu- Downloaded from Sequestration in Leishmania-infected macrophages sequester endogenously synthe- man dendritic cells. J. Leukocyte Biol. 82: 1401–1406. ϩ sized parasite antigens from presentation to CD4 T cells. Eur. J. Immunol. 26: 35. Vanloubbeeck, Y. F., A. E. Ramer, F. Jie, and D. E. Jones. 2004. CD4ϩ Th1 cells 3163–3169. induced by dendritic cell-based immunotherapy in mice chronically infected with 8. Vannier-Santos, M. A., A. Martiny, and W. de Souza. 2002. Cell biology of Leishma- Leishmania amazonensis do not promote healing. Infect. Immun. 72: 4455–4463. nia spp.: invading and evading. Curr. Pharm. Des. 8: 297–318. 36. Naderer, T., J. E. Vince, and M. J. McConville. 2004. Surface determinants of Leish- 9. Kima, P. E. 2007. The amastigote forms of Leishmania are experts at exploiting host mania parasites and their role in infectivity in the mammalian host. Curr Mol. Med. 4: cell processes to establish infection and persist. Int. J. Parasitol. 37: 1087–1096. 649–665. 10. Sacks, D., and A. Sher. 2002. Evasion of innate immunity by parasitic protozoa. Nat. 37. Brandonisio, O., R. Spinelli, and M. Pepe. 2004. Dendritic cells in Leishmania infec- http://www.jimmunol.org/ Immunol. 3: 1041–1047. tion. Microbes Infect. 6: 1402–1409. 11. Sher, A., E. Pearce, and P. Kaye. 2003. Shaping the immune response to parasites: role 38. Turco, S. J., G. F. Spath, and S. M. Beverley. 2001. Is lipophosphoglycan a virulence of dendritic cells. Curr. Opin. Immunol. 15: 421–429. factor? A surprising diversity between Leishmania species. Trends Parasitol. 17: 12. Von Stebut, E. 2007. Immunology of cutaneous leishmaniasis: the role of mast cells, 223–226. phagocytes and dendritic cells for protective immunity. Eur. J. Dermatol. 17: 39. Trinchieri, G., and A. Sher. 2007. Cooperation of Toll-like receptor signals in innate 115–122. immune defence. Nat. Rev. Immunol. 7: 179–190. 13. Ritter, U., and A. Osterloh. 2007. A new view on cutaneous dendritic cell subsets in experimental leishmaniasis. Med. Microbiol. Immunol. 196: 51–59. 40. Kropf, P., M. A. Freudenberg, M. Modolell, H. P. Price, S. Herath, S. Antoniazi, 14. Leon, B., M. Lopez-Bravo, and C. Ardavin. 2007. Monocyte-derived dendritic cells C. Galanos, D. F. Smith, and I. Muller. 2004. Toll-like receptor 4 contributes to formed at the infection site control the induction of protective T helper 1 responses efficient control of infection with the protozoan parasite Leishmania major. Infect. against Leishmania (see comment). Immunity 26: 519–531. Immun. 72: 1920–1928. 41. Flandin, J. F., F. Chano, and A. Descoteaux. 2006. RNA interference reveals a role for

15. Silveira, F. T., J. M. Blackwell, E. A. Ishikawa, R. Braga, J. J. Shaw, R. J. Quinnell, by guest on September 28, 2021 L. Soong, P. Kima, D. McMahon-Pratt, G. F. Black, and M. A. Shaw. 1998. T cell TLR2 and TLR3 in the recognition of Leishmania donovani promastigotes by inter- ␥ responses to crude and defined leishmanial antigens in patients from the lower Ama- feron- -primed macrophages. Eur. J. Immunol. 36: 411–420. zon region of Brazil infected with different species of Leishmania of the subgenera 42. Liese, J., U. Schleicher, and C. Bogdan. 2007. TLR9 signaling is essential for the in- Leishmania and Viannia. Parasite Immunol. 20: 19–26. nate NK cell response in murine cutaneous leishmaniasis. Eur. J. Immunol. 37: 16. Silveira, F. T., R. Lainson, and C. E. Corbett. 2004. Clinical and immunopathological 3424–3434. spectrum of American cutaneous leishmaniasis with special reference to the disease in 43. Colmenares, M., A. L. Corbi, S. J. Turco, and L. Rivas. 2004. The dendritic cell re- Amazonian Brazil: a review. Mem. Inst. Oswaldo Cruz 99: 239–251. ceptor DC-SIGN discriminates among species and life cycle forms of Leishmania. 17. Costa, D. J., C. Favali, J. Clarencio, L. Afonso, V. Conceicao, J. C. Miranda, J. Immunol. 172: 1186–1190. R. G. Titus, J. Valenzuela, M. Barral-Netto, A. Barral, and C. I. Brodskyn. 2004. 44. Caparros, E., D. Serrano, A. Puig-Kroger, L. Riol, F. Lasala, I. Martinez, Lutzomyia longipalpis salivary gland homogenate impairs cytokine production and co- F. Vidal-Vanaclocha, R. Delgado, J. L. Rodriguez-Fernandez, L. Rivas, et al. 2005. stimulatory molecule expression on human monocytes and dendritic cells. Infect. Im- Role of the C-type lectins DC-SIGN and L-SIGN in Leishmania interaction with host mun. 72: 1298–1305. phagocytes. Immunobiology 210: 185–193. 18. Andrade, B. B., C. I. de Oliveira, C. I. Brodskyn, A. Barral, and M. Barral-Netto. 45. Garg, R., N. Trudel, and M. J. Tremblay. 2007. Consequences of the natural propen- 2007. Role of sand fly saliva in human and experimental leishmaniasis: current in- sity of Leishmania and HIV-1 to target dendritic cells. Trends Parasitology 23: sights. Scand. J. Immunol. 66: 122–127. 317–324. 19. Beil, W. J., G. Meinardus-Hager, D. C. Neugebauer, and C. Sorg. 1992. Differences 46. Woelbing, F., S. L. Kostka, K. Moelle, Y. Belkaid, C. Sunderkoetter, S. Verbeek, in the onset of the inflammatory response to cutaneous leishmaniasis in resistant and A. Waisman, A. P. Nigg, J. Knop, M. C. Udey, and E. von Stebut. 2006. Uptake of susceptible mice. J. Leukocyte Biol. 52: 135–142. Leishmania major by dendritic cells is mediated by Fc-␥ receptors and facilitates ac- 20. Charmoy, M., R. Megnekou, C. Allenbach, C. Zweifel, C. Perez, K. Monnat, quisition of protective immunity. J. Exp. Med. 203: 177–188. M. Breton, C. Ronet, P. Launois, and F. Tacchini-Cottier. 2007. Leishmania major 47. Wanasen, N., L. Xin, and L. Soong. Pathogenic role of B cells and antibodies in mu- induces distinct neutrophil phenotypes in mice that are resistant or susceptible to in- rine Leishmania amazonensis infection. Int. J. Parasitol. In press. fection J. Leukocyte Biol. 82: 288–284. 48. Prina, E., S. Z. Abdi, M. Lebastard, E. Perret, N. Winter, and J. C. Antoine. 2004. 21. van Zandbergen, G., M. Klinger, A. Mueller, S. Dannenberg, A. Gebert, W. Solbach, Dendritic cells as host cells for the promastigote and amastigote stages of Leishmania and T. Laskay. 2004. Cutting edge: neutrophil granulocyte serves as a vector for Leish- amazonensis: the role of opsonins in parasite uptake and dendritic cell maturation. mania entry into macrophages. J. Immunol. 173: 6521–6525. J. Cell Sci. 117: 315–325. 22. Gueirard, P., A. Laplante, C. Rondeau, G. Milon, and M. Desjardins. 2008. Traffick- ing of Leishmania donovani promastigotes in non-lytic compartments in neutrophils 49. Yang, Z., D. M. Mosser, and X. Zhang. 2007. Activation of the MAPK, ERK, fol- enables the subsequent transfer of parasites to macrophages. Cell Microbiol. 10: lowing Leishmania amazonensis infection of macrophages. J. Immunol. 178: 100–111. 1077–1085. 23. Schleicher, U., J. Liese, I. Knippertz, C. Kurzmann, A. Hesse, A. Heit, J. A. Fischer, 50. Ghosh, M., L. Mandal, S. Maitra, S. Rakshit, K. Paul, J. Bagchi, D. Ganguly, C. Pal, and S. Bandyopadhyay. 2006. Leishmania donovani infection of human myeloid den- S. Weiss, U. Kalinke, S. Kunz, and C. Bogdan. 2007. NK cell activation in visceral ϩ leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasma- dritic cells leads to a Th1 response in CD4 T cells from healthy donors and patients cytoid DCs. J. Exp. Med. 204: 893–906. with Kala-Azar. J. Infect. Dis. 194: 294–301. 24. Remer, K. A., C. Apetrei, T. Schwarz, C. Linden, and H. Moll. 2007. Vaccination 51. Nigg, A. P., S. Zahn, D. Ruckerl, C. Holscher, T. Yoshimoto, J. M. Ehrchen, with plasmacytoid dendritic cells induces protection against infection with Leishmania F. Wolbing, M. C. Udey, and E. von Stebut. 2007. Dendritic cell-derived IL-12p40 major in mice. Eur. J. Immunol. 37: 2463–2473. homodimer contributes to susceptibility in cutaneous leishmaniasis in BALB/c mice. 25. Bajenoff, M., B. Breart, A. Y. C. Huang, H. Qi, J. Cazareth, V. M. Braud, J. Immunol. 178: 7251–7258. R. N. Germain, and N. Glaichenhaus. 2006. Natural killer cell behavior in lymph 52. Miles, S. A., S. M. Conrad, R. G. Alves, S. M. Jeronimo, and D. M. Mosser. 2005. A nodes revealed by static and real-time imaging. J. Exp. Med. 203: 619–631. role for IgG immune complexes during infection with the intracellular pathogen 26. Misslitz, A. C., K. Bonhagen, D. Harbecke, C. Lippuner, T. Kamradt, and Leishmania. J. Exp. Med. 201: 747–754. T. Aebischer. 2004. Two waves of antigen-containing dendritic cells in vivo in exper- 53. Besteiro, S., R. A. Williams, G. H. Coombs, and J. C. Mottram. 2007. Protein turn- imental Leishmania major infection. Eur. J. Immunol. 34: 715–725. over and differentiation in Leishmania. Int. J. Parasitol. 37: 1063–1075. 4360 BRIEF REVIEWS: MODULATING DC FUNCTION BY LEISHMANIA PARASITES

54. Ueda-Nakamura, T., M. Attias, and W. de Souza. 2007. Comparative analysis of me- 61. Ramirez-Pineda, J. R., A. Frohlich, C. Berberich, and H. Moll. 2004. Dendritic cells gasomes in members of the Leishmania mexicana complex. Res. Microbiol. 158: (DC) activated by CpG DNA ex vivo are potent inducers of host resistance to an 456–462. intracellular pathogen that is independent of IL-12 derived from the immunizing DC. 55. de Matos Guedes, H. L., M. P. D. Carneiro, D. C. de Oliveira Gomes, J. Immunol. 172: 6281–6289. B. Rossi-Bergmann, and S. G. de Simone. 2007. Oligopeptidase B from L. amazonen- 62. Carrion, J., A. Nieto, M. Soto, and C. Alonso. 2007. Adoptive transfer of dendritic sis: molecular cloning, gene expression analysis and molecular model. Parasitol. Res. cells pulsed with Leishmania infantum nucleosomal histones confers protection against 101: 866–875. cutaneous leishmaniosis in BALB/c mice. Microbes Infect. 9: 735–743. 56. Cameron, P., A. McGachy, M. Anderson, A. Paul, G. H. Coombs, J. C. Mottram, 63. Fajardo-Moser, M., S. Berzel, and H. Moll. 2008. Mechanisms of dendritic cell-based J. Alexander, and R. Plevin. 2004. Inhibition of lipopolysaccharide-induced macro- vaccination against infection. Int. J. Med. Microbiol. 298: 11–20. phage IL-12 production by Leishmania mexicana amastigotes: the role of cysteine pep- 64. Ji, J., J. Sun, H. Qi, and L. Soong. 2002. Analysis of T helper cell responses during tidases and the NF-␬B signaling pathway. J. Immunol. 173: 3297–3304. infection with Leishmania amazonensis. Am. J. Trop. Med. Hyg. 66: 338–345. 57. Saravia, N. G., B. Escorcia, Y. Osorio, L. Valderrama, D. Brooks, L. Arteaga, 65. Svensson, M., and P. M. Kaye. 2006. Stromal-cell regulation of dendritic-cell differ- G. Coombs, J. Mottram, and B. L. Travi. 2006. Pathogenicity and protective immu- entiation and function. Trends Immunol. 27: 580–587. nogenicity of cysteine proteinase-deficient mutants of Leishmania mexicana in non- 66. Zubairi, S., S. L. Sanos, S. Hill, and P. M. Kaye. 2004. Immunotherapy with murine models. Vaccine 24: 4247–4259. OX40L-Fc or anti-CTLA-4 enhances local tissue responses and killing of Leishmania 58. Ato, M., S. Stager, C. R. Engwerda, and P. M. Kaye. 2002. Defective CCR7 expres- donovani. Eur. J. Immunol. 34: 1433–1440. sion on dendritic cells contributes to the development of visceral leishmaniasis. Nat. 67. Field, A. E., S. Wagage, S. M. Conrad, and D. M. Mosser. 2007. Reduced pathology Immunol. 3: 1185–1191. following infection with transgenic Leishmania major expressing murine CD40 li- 59. Steigerwald, M., and H. Moll. 2005. Leishmania major modulates chemokine and gand. Infect. Immun. 75: 3140–3149. chemokine receptor expression by dendritic cells and affects their migratory capacity. 68. Robinson, K. A., S. Goyard, and S. M. Beverley. 2004. In vitro shuttle mutagenesis Infect. Immun. 73: 2564–2567. using engineered mariner transposons. Methods Mol. Biol. 270: 299–318. 60. Berberich, C., J. R. Ramirez-Pineda, C. Hambrecht, G. Alber, Y. A. Skeiky, and 69. Dutta, S., D. Ray, B. K. Kolli, and K. P. Chang. 2005. Photodynamic sensitization of H. Moll. 2003. Dendritic Cell (DC)-based protection against an intracellular patho- Leishmania amazonensis in both extracellular and intracellular stages with aluminum gen is dependent upon DC-derived IL-12 and can be induced by molecularly defined phthalocyanine chloride for photolysis in vitro. Antimicrob. Agents Chemother. 49: antigens. J. Immunol. 170: 3171–3179. 4474–4484. Downloaded from http://www.jimmunol.org/ by guest on September 28, 2021