Impairment of dendritic cell function by excretory‐secretory products: A potential mechanism for nematode‐induced immunosuppression

Segura, Mariela; Su, Zhendong; Piccirillo, Ciriaco A.; Stevenson, Mary M.

doi:10.1002/eji.200636553

Cited by 176 publications

(165 citation statements)

References 70 publications

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“…DCs typically acquire regulatory properties in the presence of TGF-b (47). Although the effect of HES in our in vitro cocultures was mainly on the T cells, H. polygyrus and the excretory-secretory products are also know to facilitate regulatory and Th2-promoting DC (31,(48)(49)(50). Interestingly, we found that preconditioning the site of BCG infection with TGF-b or HES significantly reduced BCGtriggered migration of DC (MHC-II hi CD11c +/int cells) to the draining LN.…”

Section: Discussionmentioning

confidence: 68%

Chronic Gastrointestinal Nematode Infection Mutes Immune Responses to Mycobacterial Infection Distal to the Gut

Obieglo

Feng

Bollampalli

et al. 2016

The Journal of Immunology

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Helminth infections have been suggested to impair the development and outcome of Th1 responses to vaccines and intracellular microorganisms. However, there are limited data regarding the ability of intestinal nematodes to modulate Th1 responses at sites distal to the gut. In this study, we have investigated the effect of the intestinal nematode Heligmosomoides polygyrus bakeri on Th1 responses to Mycobacterium bovis bacillus Calmette–Guérin (BCG). We found that H. polygyrus infection localized to the gut can mute BCG-specific CD4+ T cell priming in both the spleen and skin-draining lymph nodes. Furthermore, H. polygyrus infection reduced the magnitude of delayed-type hypersensitivity (DTH) to PPD in the skin. Consequently, H. polygyrus–infected mice challenged with BCG had a higher mycobacterial load in the liver compared with worm-free mice. The excretory–secretory product from H. polygyrus (HES) was found to dampen IFN-γ production by mycobacteria-specific CD4+ T cells. This inhibition was dependent on the TGF-βR signaling activity of HES, suggesting that TGF-β signaling plays a role in the impaired Th1 responses observed coinfection with worms. Similar to results with mycobacteria, H. polygyrus–infected mice displayed an increase in skin parasite load upon secondary infection with Leishmania major as well as a reduction in DTH responses to Leishmania Ag. We show that a nematode confined to the gut can mute T cell responses to mycobacteria and impair control of secondary infections distal to the gut. The ability of intestinal helminths to reduce DTH responses may have clinical implications for the use of skin test–based diagnosis of microbial infections.

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Section: Discussionmentioning

confidence: 68%

Chronic Gastrointestinal Nematode Infection Mutes Immune Responses to Mycobacterial Infection Distal to the Gut

Obieglo

Feng

Bollampalli

et al. 2016

The Journal of Immunology

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“…Heligmosomoides polygyrus excretory-secretory products (HES) modulate the host immune response and suppress Th2-mediated inflammation by a number of mechanisms (outlined in Figure 7), including: a) Inhibition of dendritic cell responsiveness to stimulation 25 , b) induction of CD4 +…”

Section: Discussionmentioning

confidence: 99%

Cultivation of <em>Heligmosomoides Polygyrus:</em> An Immunomodulatory Nematode Parasite and its Secreted Products

Johnston

Robertson

Harcus

et al. 2015

JoVE

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Heligmosomoides polygyrus (formerly known as Nematospiroides dubius, and also referred to by some as H. bakeri) is a gastrointestinal helminth that employs multiple immunomodulatory mechanisms to establish chronic infection in mice and closely resembles prevalent human helminth infections. H. polygyrus has been studied extensively in the field of helminth-derived immune regulation and has been found to potently suppress experimental models of allergy and autoimmunity (both with active infection and isolated secreted products). The protocol described in this paper outlines management of the H. polygyrus life cycle for consistent production of L3 larvae, recovery of adult parasites, and collection of their excretory-secretory products (HES).

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“…A feature shared by many helminths is their capacity to suppress TLR-mediated DC activation by microbial PAMP. Numerous studies have reported the inhibitory effects of helminth-derived components on TLR-induced activation as determined by pro-inflammatory cytokine production and expression of MHC class II/costimulatory molecules [28,[33][34][35][36][37][38][39]. The pathways underlying this suppression are, however, still poorly understood.…”

Section: Modulation Of DC Function By Direct Interaction With Helmintmentioning

confidence: 99%

“…Yet, little is known about the role of DC during helminth infections in this phenomenon and the underlying molecular mechanisms. The few reports that have identified helminth-derived components that directly act on DC to drive IL-10-producing adaptive Treg (Tr1 cells) [12,34] did not address the molecular mechanisms by which DC prime regulatory responses. Apart from helminthderived products, host-derived cytokines such as IL-10 and TGF-b, or apoptotic cells generated during helminth infections are likely to play an important role in DC-driven Treg induction.…”

Section: Mechanisms Behind Dc-driven Treg Inductionmentioning

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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Impairment of dendritic cell function by excretory‐secretory products: A potential mechanism for nematode‐induced immunosuppression

Cited by 176 publications

References 70 publications

Chronic Gastrointestinal Nematode Infection Mutes Immune Responses to Mycobacterial Infection Distal to the Gut

Chronic Gastrointestinal Nematode Infection Mutes Immune Responses to Mycobacterial Infection Distal to the Gut

Cultivation of <em>Heligmosomoides Polygyrus:</em> An Immunomodulatory Nematode Parasite and its Secreted Products

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

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