Invited ReviewDendritic cell activation and function in response to Schistosoma mansoni
Introduction
Schistosome infection presents a complex challenge to the immune system. The parasite is a multicellular organism which exists in discrete life stages and inhabits multiple locations within the host. The outcome of the immune response determines the balance between protective immunity and immunopathology, the difference between health and morbidity (Pearce and MacDonald, 2002). Dendritic cells (DC) are central players in the control of developing immune responses, specialised in both the initiation and polarisation of adaptive immunity (Banchereau et al., 2000; Moser and Murphy, 2000). Here, we present an overview of current understanding of the interactions between DC and schistosomes, emphasising the distinctive DC phenotypes elicited by schistosome components and the potent ability of these cells to drive T helper cell (Th) type 2 immunity in vivo.
‘Immature’ DC are often described as the sentry guards of the immune system, stationed throughout the peripheral tissues, continuously sampling their environment through phagocytosis, endocytosis and macropinocytosis (Sallusto et al., 1995; Winzler et al., 1997). They filter soluble antigens from extracellular fluid at such a rate that they internalise the equivalent of their own volume within 2 h (Sallusto et al., 1995).
Recent years have seen the description of a plethora of defined pattern recognition receptors (PRRs) expressed by DC that can recognise and bind with pathogen-associated molecular patterns (PAMPs) displayed by infectious organisms such as bacteria and viruses (Janeway, 1989). If ‘danger’ signals are encountered by DC in the form of PAMPs, inflammatory cytokines or signals from activated T cells, a process of classical ‘maturation’ is triggered and they transform from dedicated antigen (Ag) collectors into specialised Ag presenting cells (APC) (Matzinger, 2002). DC migration towards naïve T cells in the draining lymph node (LN) is accompanied by a significant up-regulation and stabilisation of surface major histocompatability molecules (MHC) (Cella et al., 1997; Pierre et al., 1997), increased expression of key costimulatory molecules such as CD80 and CD86, intracellular adhesion molecule-1 (ICAM-1) and CD40 and an enhanced readiness to secrete T cell stimulatory cytokines such as IL-12 (Kang et al., 1996; Reis e Sousa et al., 1997) and IL-2 (Granucci et al., 2001). The result is a potent APC, equipped to interact with and activate naïve T cells (Bhardwaj et al., 1993; Sallusto et al., 1995).
The best studied examples of the PRRs are provided by the Toll-like receptors (TLRs), a family of proteins largely responsible for triggering conventional maturation in dendritic cells exposed to proinflammatory, Th1-driving pathogens (Akira and Takeda, 2004; Beutler, 2004). Whether a set of equivalent but Th2-polarising receptors will be uncovered or whether the existing TLRs are sufficient to orchestrate both types of response is still a matter of debate. In addition to TLRs, recognition of Ag by DC is also mediated by C-type lectins such as DC-specific intracellular adhesion molecule three grabbing nonintegrin (DC-SIGN or CD209), DEC-205 (CD205) and Dectin-1 (Figdor et al., 2002; Geijtenbeek et al., 2003; van Kooyk and Geijtenbeek, 2003; Rogers et al., 2005). Interestingly, there is evidence that signaling via C-type lectins may in some cases inhibit DC maturation, a feature that appears to have been exploited by certain pathogens (Geijtenbeek et al., 2003).
In the past few years, it has become clear that the paradigm of the conventionally mature, immunogenic DC is not always a valid one. Different DC phenotypes can direct immune responses as diverse as immunity and tolerance (Lutz and Schuler, 2002). Several main subpopulations of DC exist, identified on the basis of expression of particular surface markers and isolated from specific tissues; ‘lymphoid’ (CD11c+/CD8α+), ‘myeloid’ (CD11c+/CD8α−) and ‘plasmacytoid’ (CD11c+/B220+) DC. Initial experiments suggested that different lineages possessed distinct functions that preferentially induced either Th1 or Th2 responses (often termed ‘DC1’ and ‘DC2’) (Maldonado-Lopez et al., 1999; Pulendran et al., 1999; Rissoan et al., 1999; Shortman and Liu, 2002). More recent work, focussing on the DC response to pathogen-derived rather than model antigens, has revealed that, while DC subsets may differ in the limits of their possible function, all are capable of assessing the nature and context of an Ag and tailoring the immune response appropriately (Kalinski et al., 1999; Kapsenberg, 2003; Manickasingham et al., 2003). Thus, the restrictive idea of lineage determination has been largely replaced with a model of functional plasticity, in which the complex mélange of molecular information presented by pathogens is recognised and translated into polarised T cell activity by local DC. This concept of DC plasticity makes sense given that the mammalian immune system has arguably developed as a consequence of evolutionary interactions with pathogens.
Kalinski and colleagues coined the term ‘signal 3’ to describe the polarising instructions delivered to naïve T cells by DC alongside T cell receptor (TCR) engagement (‘signal 1’) and CD80/86:CD28 interaction (‘signal 2’) (Kalinski et al., 1999). Their model noted the potent ability of DC-derived IL-12 to skew towards interferon γ (IFNγ) production in responding T cells, an observation which Reis e Sousa expanded in his description of an IL-12/IL-10 axis of DC maturation: pathogen products elicit high levels of either IL-12 or IL-10 from DC and only those that generate IL-12 drive strong Th1 responses (Edwards and Reis e Sousa, 2002). Thus, the cytokines released by DC and those consequently triggered downstream appear to reflect the specific activation of these cells by distinct pathogens.
To date, our appreciation of these processes of DC activation and function remains heavily biased towards data collected in experiments focussing on model antigens or components of pathogens such as bacteria, viruses or protozoa that typically induce Th1 responses (Reis e Sousa et al., 1999). The DC response to multicellular organisms is much less understood. Of the three main human-infective species of schistosome (Schistosoma mansoni, Schistosoma hematobium and Schistosoma japonicum), the immune response to and immunopathology caused by S. mansoni has been most extensively dissected. This response is strongly Th2 in nature and detailed analysis has revealed that the major Th2 stimulating Ag are soluble and released from the egg stage (Grzych et al., 1991; Pearce et al., 1991). It is clear that the Th2 response provides protection against potentially life-threatening aspects of ongoing infection, as well as against superinfection (Brunet et al., 1998, 1999; Fallon et al., 2000; Hoffmann et al., 2000). At the same time, the Th2 response is intimately involved in the development of much of the pathology that accompanies infection, including tissue fibrosis (Pearce and MacDonald, 2002). Despite its importance, the mechanisms that control the development of the Th2 response, how it is regulated and how it serves its protective role are still largely unknown (Pearce and MacDonald, 2002).
Section snippets
The dendritic cell: parasite interface
Several years ago, we set out to address the fundamental immunological question of how DC respond to Th2-inducing pathogens and, mechanistically, how they subsequently initiate and direct the Th2 response, focussing on the murine response to S. mansoni.
The interaction between parasite and DC begins with recognition of specific components of the antigenic mix encountered by the host. All life cycle stages of S. mansoni produce a complex range of molecules—proteins, carbohydrates and lipids—some
Dendritic cell activation by S. mansoni
Of all the life cycle stages of S. mansoni, we currently know the most about the ability of soluble egg Ag (SEA) to influence DC activation. SEA is a complex mix of diverse components that is crudely analogous to the metabolic secretions of live eggs. Notably, each of SEA, live or dead S. mansoni eggs provoke a striking Th2 response when injected directly into naïve recipient mice, without the need for additional adjuvant. Indeed SEA, like some other helminth products or extracts (Holland et
T cell activation and polarisation by dendritic cells responding to S. mansoni
Around the time that data were emerging describing the subdued activation of DC by schistosome Ag, a new facet of DC biology was also being described—their ability in certain settings to be tolerogenic rather than immunogenic (Lutz and Schuler, 2002; Steinman et al., 2003). This was noted when DC were exposed to Ag that did not provide activatory ‘danger’ signals such as apoptotic cells or commensal bacteria. Notably, such DC failed to show overt signs of conventional maturation, which was
DC, S. mansoni, and ‘default’ Th2 reponse development
One proposal has been that Th2 induction by DC occurs via a default pathway that develops in the absence of Th1 driving stimuli, particularly IL-12 (Moser and Murphy, 2000; Eisenbarth et al., 2003). Such a passive situation may occur when DC and T cells are co-cultured in vitro, especially when DC are exposed to model Ag that do not express pathogenic PAMPS. However, since this passive model for Th2 induction was introduced, our understanding of the critical contribution that the type of
Conclusions
It is clear that schistosomes fail to conventionally activate DC either in vitro, or during active infection. Irrespective of this (and contrary to prevailing dogma) these DC can capably stimulate naïve T cells, and drive then towards a Th2 phenotype. Based on our initial studies with SEA, we originally proposed that a lack of conventional DC activation might be a feature of DC responses to schistosomes, and perhaps other helminths and Th2 development in general (MacDonald et al., 2001).
Acknowledgements
Andrew MacDonald's laboratory is supported by the MRC (UK) and the Wellcome Trust.
References (100)
- et al.
Double-stranded RNAs from the Helminth Parasite Schistosoma activate TLR3 in dendritic cells
J. Biol. Chem.
(2005) - et al.
Cytokine interaction and immune responses during Schistosoma mansoni infection
Parasitol. Today
(1998) - et al.
Ox40-ligand has a critical costimulatory role in dendritic cell:T cell interactions
Immunity
(1999) - et al.
The master regulators of allergic inflammation: dendritic cells in Th2 sensitization
Curr. Opin. Immunol.
(2003) - et al.
Th1/Th2 effector choice in parasitic infection: decision making by committee
Curr. Opin. Immunol.
(2001) - et al.
In the absence of IL-12, CD4(+) T cell responses to intracellular pathogens fail to default to a Th2 pattern and are host protective in an IL-10(−/−) setting
Immunity
(2002) - et al.
T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal
Immunol. Today
(1999) - et al.
Unresponsiveness of MyD88-deficient mice to endotoxin
Immunity
(1999) - et al.
Regulation of T cell immunity by dendritic cells
Cell
(2001) - et al.
Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?
Trends Immunol.
(2002)
DC-SIGN mediates binding of dendritic cells to authentic pseudo-LewisY glycolipids of Schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN
J. Biol. Chem.
Progress towards a vaccine for schistosomiasis
Acta Trop.
The role of dendritic cells in the induction and regulation of immunity to microbial infection
Curr. Opin. Immunol.
Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins
Immunity
Molecular characterization of an interleukin-4-inducing factor from Schistosoma mansoni eggs
J. Biol. Chem.
A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates toll-like receptor 2 and affects immune polarization
J. Biol. Chem.
Cutting edge: different toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos
J. Immunol.
Toll-like receptor signalling
Nat. Rev. Immunol.
Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection
J. Exp. Med.
Dendritic cell-intrinsic expression of NF-kappa B1 is required to promote optimal Th2 cell differentiation
J. Immunol.
Selective maturation of dendritic cells by Nippostrongylus brasiliensis-secreted proteins drives Th2 immune responses
Eur. J. Immunol.
Immunobiology of dendritic cells
Annu. Rev. Immunol.
Help for cytotoxic-T-cell responses is mediated by CD40 signalling
Nature
Inferences, questions and possibilities in Toll-like receptor signalling
Nature
Small amounts of superantigen, when presented on dendritic cells, are sufficient to initiate T cell responses
J. Exp. Med.
Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation
J. Exp. Med.
Schistosoma mansoni: IL-4 is necessary for concomitant immunity in mice
J. Parasitol.
Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation
J. Exp. Med.
Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells
Nature
Cutting edge: dendritic cells copulsed with microbial and helminth antigens undergo modified maturation, segregate the antigens to distinct intracellular compartments, and concurrently induce microbe-specific Th1 and helminth-specific Th2 responses
J. Immunol.
Regulatory activity of autocrine IL-10 on dendritic cell functions
J. Immunol.
Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans. Implications for initiation of T helper cell immunity in vitro and in vivo
J. Exp. Med.
Microbial compounds selectively induce Th1 cell-promoting or Th2 cell-promoting dendritic cells in vitro with diverse th cell-polarizing signals
J. Immunol.
In vivo triggering through 4-1BB enables Th-independent priming of CTL in the presence of an intact CD28 costimulatory pathway
J. Immunol.
A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells
J. Immunol.
Microbial recognition via Toll-like receptor-dependent and -independent pathways determines the cytokine response of murine dendritic cell subsets to CD40 triggering
J. Immunol.
Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent
J. Immunol.
Schistosome N-glycans containing core alpha 3-fucose and core beta 2-xylose epitopes are strong inducers of Th2 responses in mice
Eur. J. Immunol.
C-type lectin receptors on dendritic cells and langerhans cells
Nat. Rev. Immunol.
Mycobacteria target DC-SIGN to suppress dendritic cell function
J. Exp. Med.
Inducible IL-2 production by dendritic cells revealed by global gene expression analysis
Nat. Immunol.
Measles virus infects human dendritic cells and blocks their allostimulatory properties for CD4+T cells
J. Exp. Med.
Egg deposition is the major stimulus for the production of Th2 cytokines in murine schistosomiasis mansoni
J. Immunol.
Experimental murine schistosomiasis in the absence of B7 costimulatory molecules: reversal of elicited T cell cytokine profile and partial inhibition of egg granuloma formation
J. Immunol.
IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis
J. Immunol.
Interleukin-12 p40 secretion by cutaneous CD11c+ and F4/80+ cells is a major feature of the innate immune response in mice that develop Th1-mediated protective immunity to Schistosoma mansoni
Infect. Immun.
IL-10 regulates early IL-12-mediated immune responses induced by the radiation-attenuated schistosome vaccine
Int. Immunol.
Proteins secreted by the parasitic nematode Nippostrongylus brasiliensis act as adjuvants for Th2 responses
Eur. J. Immunol.
Approaching the asymptote? Evolution and revolution in immunology
Cold Spring Harb. Symp. Quant. Biol.
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