<i>Brugia malayi</i>Microfilariae Induce Cell Death in Human Dendritic Cells, Inhibit Their Ability to Make IL-12 and IL-10, and Reduce Their Capacity to Activate CD4+ T Cells

Semnani, Roshanak Tolouei; Liu, Anne Y.; Sabzevari, Helen; Kubofcik, Joseph; Zhou, Jun; Gilden, Julia; Nutman, Thomas B.

doi:10.4049/jimmunol.171.4.1950

Cited by 107 publications

(120 citation statements)

References 41 publications

(28 reference statements)

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“…In addition, our results using HLA-DR blockade demonstrate that Ag presentation is mandatory for T cell induction of cytokines. Studies in murine models of filariasis indicate that a proinflammatory response is induced in macrophages by the Wolbachia endosymbiont of filarial parasites (34); however, our LPS inhibition studies with both polymyxin B (20) and rBPI (21) and the studies using neutralization of TLR4 and TLR2, known to completely inhibit effects of LPS-like molecules (22), exclude a significant role for Wolbachia in the proinflammatory T cell response observed in this in vitro system. Moreover, the use of live L3 (rather than Ag) increases the likelihood that the intracellular Wolbachia are unlikely to provide a source of LPS.…”

Section: Discussioncontrasting

confidence: 42%

Proinflammatory Cytokines Dominate the Early Immune Response to Filarial Parasites

Babu

Nutman

2003

The Journal of Immunology

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Although the early human immune response to the infective-stage larvae (L3) of Brugia malayi has not been well-characterized in vivo (because of the inability to determine the precise time of infection), the consensus has been that it must involve a predominant Th2 environment. We have set up an in vitro system to study this early immune response by culturing PBMC from unexposed individuals with live L3 of B. malayi. After 24 h of culture, T cell responses were examined by flow cytometry and by quantitative real-time RT-PCR for multiple cytokines. T cells were activated early following exposure to L3 as indicated by up-regulation of surface markers CD69 and CD71. The frequency of T cells expressing proinflammatory Th1 cytokines (IFN-γ, TNF-α, GM-CSF, IL-1α, and IL-8) but not Th2 cytokines (IL-4, IL-5, IL-6, IL-10, and IL-13) was significantly increased in response to L3. This T cell response occurred in both the CD4 and CD8 T cell compartment and was restricted to the effector/memory pool (CD45RO+). This T cell response was not due to LPS activity from the parasite or from its endosymbiont, Wolbachia; moreover, it required the presence of APC as well as direct contact with live L3. Real-time RT-PCR analysis of multiple cytokines in the T cells confirmed the increased expression of proinflammatory Th1 cytokines. Up-regulation of these cytokines suggests that the primary immune response to the live infective stage of the parasite is not predominantly Th2 in nature but rather dominated by a proinflammatory response.

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Section: Discussioncontrasting

confidence: 42%

Proinflammatory Cytokines Dominate the Early Immune Response to Filarial Parasites

Babu

Nutman

2003

The Journal of Immunology

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“…injection of Mf have shown that they induce apoptosis of T cells in a NO-dependent manner (29 -31). Mf Ags have also been shown to inhibit the in vitro maturation and function of human dendritic cells (DC), resulting in impaired T cell priming (32)(33)(34). Together, these studies indicate that filarial suppression acts on multiple cell types within the immune response, and that additional mechanisms of suppression may by invoked by each stage of the life cycle.…”

mentioning

confidence: 85%

F4/80+ Alternatively Activated Macrophages Control CD4+ T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection

Taylor

Harris

Nair

et al. 2006

The Journal of Immunology

105

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Both T cells and APC have been strongly implicated in the immune suppression observed during filarial nematode infections, but their relative roles are poorly understood, particularly in regard to timing and locality of action. Using Litomosoides sigmodontis infection of susceptible BALB/c mice, we have studied the progression of filarial immunosuppression leading to patent infection with blood microfilaremia. Patent infection is associated with decreased immune responsiveness in the draining thoracic lymph nodes (tLN) and intrinsically hyporesponsive CD4+ T cells at the infection site. We now show that we are able to separate, both in time and space, different suppressive mechanisms and cell populations that contribute to filarial hyporesponsiveness. L. sigmodontis infection recruited a F4/80+ population of alternatively activated macrophages that potently inhibited Ag-specific CD4+ T cell proliferative responses even in the presence of competent naive APC. T cell responsiveness was partially restored by neutralizing TGF-β, but not by blocking IL-10 or CTLA-4 signaling. During prepatent infection, the macrophage population was restricted to the infection site. However, once infection became patent with systemic release of microfilariae, the suppressive macrophage activity extended peripherally into the tLN. In contrast, the hyporesponsive CD4+ T cell phenotype remained localized at the infection site, and the tLN CD4+ T cell population recovered full Ag responsiveness in the absence of suppressive macrophages. Filarial immunosuppression, therefore, evolves over time at sites increasingly distal to infection, and the mechanisms of filarial down-regulation are dependent on proximity to the infection site.

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“…As such, this pathway may represent an important component of the regulatory responses observed during helminth infections. In fact, since it is known that filarial parasites have the capacity to directly induce apoptosis of DC [70,71], it is tempting to speculate that some helminths may even exploit this mechanism of apoptosis-mediated immune regulation to subvert immune responses.…”

Section: Apoptosis and Nutritionmentioning

confidence: 99%

Helminths and dendritic cells: Sensing and regulating via pattern recognition receptors, Th2 and Treg responses

et al. 2010

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The classical reaction of the host to helminth infections is the induction of Th2 immune responses with a regulatory component. DC, as central players in the induction and maintenance of immune responses, play a prominent role in both these processes, and in recent years considerable progress has been made in elucidating the mechanisms behind the interplay between DC and helminths. It is becoming increasingly clear that helminths modulate DC function not only via direct interactions but also indirectly via host-derived cues. Furthermore, while studies have until recently focused on receptor signalingmediated DC modulation by helminths, evidence is emerging that DC may also respond to helminth infections by sensing stress signals or tissue damage inflicted by the worms or their products. Here, we will discuss these new insights and will link them to the origin and importance of Th2 and regulatory immune responses with respect to the survival of both parasite and host.Key words: DC . Helminth . Th cell polarization . Tissue damage IntroductionThe classical reaction of the host to helminth infections is the induction of Th2 responses. The induction of Th2 immunity has been shown to be important for resistance to helminth infections in various model systems; however, despite induction of a Th2 response, total clearance of the parasites rarely occurs in man (reviewed in [1,2]). This implies that helminths have evolved strategies, such as evasion or suppression of the host immune response that prevent their expulsion and permit their long-term survival. The immune modulatory effects are thought to arise from the helminth's capacity to exploit the host's own system of immune regulation, which is normally crucial for the maintenance of immune homeostasis and self tolerance. In this respect, the induction of Treg has been shown to be one of the most common mechanisms that restrains immune responses against the parasite while also preventing excessive inflammation and tissue damage inflicted by the worms (reviewed in [2,3]). Therefore, it is not surprising that among the variety of mechanisms developed by helminths to influence host immune responses, modulation of DC as pivotal players in the initiation and polarization of adaptive immune responses, including Treg modulation, may have a particularly important role (reviewed in [2,4,5] ) carbohydrate epitope found in schistosoma soluble egg antigens (SEA), has been implicated in TLR4-dependent priming of Th2 responses via DC [9]. However, SEA is also known to be capable of modulating DC for Th2 priming in the absence of TLR signaling [10]. Furthermore, phosphatidylserine (PS) lipids derived from schistosomes and ascaris worms, which carry TLR2-activating molecules, have been shown to promote Th2 responses via DC, but this is not TLR2 dependent [11], whereas monoacetylated PS lipids from schistosomes were found to specifically instruct DC to preferentially induce IL-10-producing Treg in a TLR2-dependent fashion [12]. Although TLR2 does not seem to be essential for Th2 polar...

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Brugia malayiMicrofilariae Induce Cell Death in Human Dendritic Cells, Inhibit Their Ability to Make IL-12 and IL-10, and Reduce Their Capacity to Activate CD4+ T Cells

Cited by 107 publications

References 41 publications

Proinflammatory Cytokines Dominate the Early Immune Response to Filarial Parasites

Proinflammatory Cytokines Dominate the Early Immune Response to Filarial Parasites

F4/80+ Alternatively Activated Macrophages Control CD4+ T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection

Helminths and dendritic cells: Sensing and regulating via pattern recognition receptors, Th2 and Treg responses

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