Dendritic cells, but not macrophages, produce IL-12 immediately following Leishmania donovani infection

Gorak, Patricia M. A.; Engwerda, Christian R.; Kaye, Paul M.

doi:10.1002/(sici)1521-4141(199802)28:02<687::aid-immu687>3.3.co;2-e

Cited by 127 publications

(193 citation statements)

References 32 publications

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“…3B, there was a 16-fold induction of IL-12p40 mRNA at 8 h of infection with promastigotes alone, but a less than 4-fold induction following infection with amastigotes. Notably, the expression levels in both groups dropped dramatically at 24 h post-infection, confirming the transient induction of IL-12p40 gene during Leishmania infection (Gorak et al, 1998). The levels of IL-12p35 mRNA were below the detection limit in DCs infected with parasites alone.…”

Section: Down-regulation Of Il-12 Production By La Parasites At Gene mentioning

confidence: 53%

“…Infection with L. major or L. donovani pro-or amastigotes, DCs can induce IL-12p40 production in vitro and in vivo (Bennett et al, 2001;Gorak et al, 1998;Konecny et al, 1999). However, we found that La promastigotes only weakly induced IL-12p40 production, whereas infection of amastigotes was devoid of this response (Fig.3B).…”

Section: Discussionmentioning

confidence: 73%

“…However, studies from our and other groups have revealed marked differences in DC responsiveness to Old World versus New World Leishmania parasites. For example, while appreciable levels of IL-12 are produced in murine DCs infected with L. major or L. donovani promastigotes (Gorak et al, 1998;von Stebut et al, 1998), C57BL/6 (B6) DCs infected with L. mexicana amastigotes show no sign of activation and no detectable levels of IL-12 and other proinflammatory cytokines (Bennett et al, 2001). Likewise, Leishnahia amazonensis (La) amastigotes failed to induce CD40-dependent IL-12 production from both BALB/c and C3H DCs (Qi et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

Luo

Soong

2008

Molecular Immunology

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We have previously reported a link between a deficient Th1 response to Leishmania amazonensis (La) parasites and profound impairments in the cytokine/chemokine network at early stages of the infection. To define the molecular basis of these deficiencies, we focused on early and intracellular events in La-infected dendritic cells (DCs) in this study. Compared with La promastigote-infected counterparts, amastigote-infected DCs were less mature and less potent as antigen-presenting cells (APC) as evidenced by the lower expression of CD40 and CD83, suppressed cytokine expression (IL-12p40 and IL-10), reduced effectiveness for priming CD4 + T cells from naïve or infected mice. Infection with La promastigotes, but not amastigotes, triggered transient expression of IL-12p40 by DC. Both forms of parasites markedly suppressed IL-12p40, IL-12p70, and IL-6 production and increased IL-10 production when DCs were treated with LPS, IFN-γ/LPS or IFN-α/LPS as positive stimuli. Of note, pre-infection of DCs with live amastigotes resulted in multiple alterations in innate signaling pathways, including degradation of STAT2, decreased phosphorylation of STAT1, 2, 3 and ERK1/2, and markedly reduced expression of interferon regulatory factor-1 (IRF-1) and IRF-8, some of which were partially reversed by pretreatment of parasites with proteasome or protease inhibitors. The impaired IL-12 production in infected DCs was not attributed to increased IL-10 production. Together, our data suggest that La parasites, especially in their intracellular forms, have evolved unique strategies to actively downregulate early innate signaling events, resulting in impaired DC function and Th1 activation.

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Section: Down-regulation Of Il-12 Production By La Parasites At Gene mentioning

confidence: 53%

Section: Discussionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

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Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

Luo

Soong

2008

Molecular Immunology

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“…MP are not the only cell type capable of producing of IL-12 and certainly it has been demonstrated that the in vivo source of IL-12 during Leishmania spp. infection is likely dendritic cells (Gorak et al, 1998;Marovich et al, 2000;McDowell et al, 2002). However, Leishmania spp.-infected dendritic cells require CD40L costimulation for IL-12 production (Marovich et al, 2000;McDowell et al, 2002), suggesting that during infection, dendritic cells initiate a protective response after interaction with antigenspecific T-cells in lymphoid tissue.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

Jayakumar

Widenmaier

et al. 2008

Journal of Parasitology

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To establish and persist within a host, Leishmania spp. parasites delay the onset of cell-mediated immunity by suppressing interleukin-12 (IL-12) production from host macrophages. Although it is established that Leishmania spp.-infected macrophages have impaired IL-12 production, the mechanisms that account for this suppression remain to be completely elucidated. Using a luciferase reporter assay assessing IL-12 transcription, we report here that Leishmania major, Leishmania donovani, and Leishmania chagasi inhibit IL-12 transcription in response to interferon-gamma, lipopolysaccharide, and CD40 ligand and that Leishmania spp. lipophosphoglycan, phosphoglycans, and major surface protein are not necessary for inhibition. In addition, all the Leishmania spp. strains and life-cycle stages tested inhibited IL-12 promoter activity. Our data further reveal that autocrineacting host factors play no role in the inhibitory response and that phagocytosis signaling is necessary for inhibition of IL-12.The hallmark of an intracellular pathogen is its ability to survive within the intracellular niche. These organisms must be resistant to, or able to evade, the host cell's microbiocidal mechanisms. This dilemma is particularly relevant to Leishmania spp. because these organisms primarily reside within vertebrate macrophages (MP). These host cells become activated for microbial destruction and cytokine secretion by exposure to immune modulators, such as interferon-gamma (IFN-γ) and CD40 ligand (CD40L) found on activated T-cells. One strategy Leishmania spp. parasites use to avoid host cell activation is to interfere with the signaling pathways that induce MP to become microbicidal (Gregory and Olivier, 2005); another is inhibiting or delaying the production of activating cytokines (Belkaid et al., 2000).The most consistent dysfunction reported from Leishmania spp.-infected MP is the aberrant production of inflammatory cytokines, specifically an inhibition of interleukin-12 (IL-12) production (McDowell and Sacks, 1999). Being essential for T-helper 1 (Th1) cell differentiation, the inability of Leishmania spp.-infected MP to produce IL-12 allows Leishmania spp. to evade acquired resistance by postponing IL-12 production and the induction of IFN-γ, thereby allowing the establishment of the infection; both clinical and experimental studies indicate that the onset of Th1-mediated immunity and Leishmania spp. killing is indeed delayed (Melby, 1991). Inhibition of MP IL-12 production and resulting Th1 responses is not unique to Leishmania; viruses (Chehimi et al., 1994;Chougnet et al., 1996;Karp et 1996) and bacteria (Marth and Kelsall, 1997;Sutterwala et al., 1997;Matsunaga et al., 2003) also exploit this mechanism to avoid clearance.The general nature of impaired IL-12 production in Leishmania spp.-infected MP has extended to every IL-12 agonist that has been tested. Leishmania spp.-infected MP are unable to produce IL-12 even in response to strong inflammatory stimuli, including microbial stimuli, e.g., lipopolysacchar...

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“…Early infection is accompanied by rapid IL-12 production by DC [12], the activation of CD4 + and CD8 + T cells, and the subsequent production of a variety of Th1 and Th2 cytokines, including IL-2, IFN-c and IL-4 [13,14]. While this immune response can readily eliminate most L. donovani amastigotes from the liver of infected mice over a 50-100-day period [15], parasites persist in the spleen, and this persistence is associated with severe splenomegaly and an array of pathological changes to the splenic lymphoid microenvironment [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

The fate of heterologous CD4⁺ T cells during Leishmania donovani infection

2005

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Little is currently understood about the consequences of chronic parasitic infection for the fate of memory CD4 + T cells that recognize heterologous antigens, e.g. resulting from prior infections or vaccination. Here, we address how Leishmania donovani infection affected the fate of non-cross-reactive (OVA)-specific memory CD4 + T cells. DO11 cells were adoptively transferred into naive recipient mice, which were then immunized to generate memory DO11 cells. After 6 weeks, mice were infected with L. donovani and the fate of DO11 cells was determined. L. donovani infection stimulated an approximately threefold expansion in the total number of CD4 + T cells and DO11 cells, compared to that observed in uninfected mice. DO11 T cells were more actively dividing in infected mice, as judged by 5-bromo-2 0 deoxyuridine labeling, whereas their rate of apoptosis in control and infected mice was identical. Both CD45RB hi CD44 lo naive T cells and to a greater extent CD45RB lo CD44 hi memory DO11 cells increased in number in the spleens of infected mice, whereas no changes occurred to DO11 cell number or phenotype in the draining lymph nodes. These data indicate that heterologous CD4 + T cells may actively divide during chronic infectious diseases, with important implications for how chronic infection may impact on heterologous immunity. IntroductionThe generation of memory T cells with enhanced capacity to respond to subsequent antigen exposure is a fundamental tenet of the acquired immune response, underlying host protection associated with cure from primary infection or resulting from vaccination [1]. Nevertheless, the requirements for the maintenance of immunological memory, notably within the CD4 + T cell compartment, remain to be fully elucidated. Of particular scientific as well as practical relevance is the requirement for the maintenance of a source of cognate antigen in the long-term survival of memory T cells. While it has been established that CD8 + T cell memory may be maintained in the complete absence of antigen [2,3], fewer studies have addressed the need for cognate antigen in the maintenance of CD4 + T cell memory. CD4 + memory T cells have been shown to survive long term in the complete absence of antigen [4] or the ability to present it via MHC II [5,6], at least under conditions where competition from other T cells was minimal. However, such situations may have limited physiological importance. In a contrasting study, intermittent stimulation by persisting antigen was shown to be necessary for CD4 + memory T cell survival [7], although again competition from other T cells was not taken into account.In addition to the possible role of antigen in maintaining CD4 + T cell memory, a number of studies have suggested that the memory T cell compartment itself is of finite size, opening the way for inter-clonal competition for space within this compartment [2,8].The generalization of these observations has, however, yet to be demonstrated, and most models of clonal attrition involve viral or bacterial infectio...

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Dendritic cells, but not macrophages, produce IL-12 immediately following Leishmania donovani infection

Cited by 127 publications

References 32 publications

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

The fate of heterologous CD4⁺ T cells during Leishmania donovani infection

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Dendritic cells, but not macrophages, produce IL-12 immediately following Leishmania donovani infection

Cited by 127 publications

References 32 publications

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

The fate of heterologous CD4+ T cells during Leishmania donovani infection

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The fate of heterologous CD4⁺ T cells during Leishmania donovani infection