• DC;
  • Helminth;
  • Th cell polarization;
  • Tissue damage


  1. Top of page
  2. Abstract
  3. Introduction
  4. Modulation of DC function by direct interaction with helminth-derived molecules
  5. Endogenous factors modulating DC function during helminth infection
  6. T-cell polarization by helminth-conditioned DC
  7. Why Th2 and Treg?
  8. Concluding remarks
  9. Acknowledgements
  10. References

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 signaling-mediated 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.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Modulation of DC function by direct interaction with helminth-derived molecules
  5. Endogenous factors modulating DC function during helminth infection
  6. T-cell polarization by helminth-conditioned DC
  7. Why Th2 and Treg?
  8. Concluding remarks
  9. Acknowledgements
  10. References

The 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).

Modulation of DC function by direct interaction with helminth-derived molecules

  1. Top of page
  2. Abstract
  3. Introduction
  4. Modulation of DC function by direct interaction with helminth-derived molecules
  5. Endogenous factors modulating DC function during helminth infection
  6. T-cell polarization by helminth-conditioned DC
  7. Why Th2 and Treg?
  8. Concluding remarks
  9. Acknowledgements
  10. References

DC modulation via PRR signaling

The capacity to recognize and distinguish different classes of pathogens is of critical importance for the initiation of appropriate immune responses. For this purpose, DC express PRR, which recognize and differentiate between different pathogen-derived molecules, the so-called PAMP. One of the most thoroughly studied classes of PRR are the TLR, which have primarily been implicated in the priming of pro-inflammatory/Th1 responses by DC in response to PAMP from bacterial or viral origin 6. Nonetheless, some helminth products have also been shown to prime Th2 or regulatory responses through ligation of TLR. For instance, excretory/secretory-62 (ES-62), a phosphorylcholine-containing glycoprotein of the nematode Acanthocheilonema viteae, conditions DC to induce Th2 responses through TLR4 7, 8. Moreover, the glycoconjugate LNFPIII, carrying a Lewis-X (Lex) 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 mono-acetylated PS lipids from schistosomes were found to specifically instruct DC to preferentially induce IL-10-producing Treg in a TLR2-dependent fashion12. Although TLR2 does not seem to be essential for Th2 polarization by schistosomes in vivo10, 13, there is evidence that TLR2 plays an important role in the induction of Treg responses during natural infection 14. Finally, double-stranded RNA from schistosome eggs has been implicated in the activation of DC via TLR3, resulting in a Th1-polarized response 13, 15.

Apart from TLR, a group of carbohydrate-recognizing PRR, the C-type lectins (CLR) have been shown to play an important role in the sensing of helminth glycans by DC. For instance, SEA, which contains glycoproteins, is recognized and internalized by human DC in a DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN)-, mannose receptor- and macrophage galactose-type lectin-dependent manner 16, 17. Antigen preparations of other stages of the schistosome life cycle have also been shown to interact with DC-SIGN 18. Binding of SEA to DC-SIGN is dependent on the sugar motifs Lex and LDN-F 17, while chemical modification of the glycans present in SEA abolishes the Th2-driving capacity of SEA 19. This, together with the observation that Lex-containing LNFPIII favors Th2-biased responses 20, suggests that CLR play an important role in conditioning DC for induction of Th2 responses by schistosomal antigens. Moreover, antigens from Toxocara canis were found to be recognized by DC-SIGN expressed on DC 21, and the induction of a Th2 response in vivo by antigens of the parasitic nematode Brugia malayi, as well as the free-living nematode Caenorhabditis elegans, was found to be dependent on intact glycans 22. These findings together suggest that certain helminth glycans may serve as PAMP that instruct DC via CLR to drive Th2-polarized responses.

Finally, there is evidence that the class A scavenger receptor, which is a member of a family of receptors that bind chemically modified low-density lipoproteins, can function as PRR (reviewed in 23), and mediate recognition of helminth components that result in the induction of Th2-polarized responses. It was found that calreticulin, a secreted protein expressed by tissue-invasive larvae of the gastrointestinal helminth Heligmosomoides polygyrus, binds class A scavenger receptor on DC and has the capacity in the absence of adjuvants to predominantly induce IL-4 production in vivo24.

In contrast to the prevailing view of DC activation by microbial ligands via PRR, DC primed by helminth products often fail to show signs of classical maturation 25. The absence of DC maturation is in-line with several studies in which stimulation of p38 MAPK, a signaling molecule crucial for PRR-mediated DC activation 26, was not observed in DC exposed to helminth products such as SEA, ES-62 or LNFPIII 9, 27–29. Instead, these helminth-derived components preferentially induce the activation of ERK MAPK, in the case of SEA and ES-62, or NF-κB1 and ERK, in the case of LNFPIII. Signaling through ERK in DC has been shown to result in suppression of IL-12 and induction of IL-10 expression, in line with the observation that ERK−/− mice are prone to develop autoimmunity. As a result, ERK has been implicated in conditioning DC for Th2 priming 11, 30, 31. Likewise, signaling through NF-κB1 appears to be important for priming of DC for Th2 polarization, since both SEA- 32 and LNFPIII-pulsed NF-κB1-deficient DC 29 are incapable of inducing a Th2 response (Fig. 1).

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Figure 1. Molecular mechanisms through which DC become conditioned by helminth products via signaling-dependent and signaling-independent pathways for priming of Th2 responses. Helminth-derived molecules condition DC for induction of Th2 polarization through interactions with PRR, which in signaling-dependent fashion induce the expression of Th2-promoting molecules while suppressing the expression of Th1-polarizing factors. In addition, helminth-derived molecules may favor induction of Th2 responses by DC by suppressing antigen presentation, costimulation and/or expression of Th1-promoting cytokines by directly interfering with these pathways in a signaling-independent fashion.

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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, 33–39. The pathways underlying this suppression are, however, still poorly understood. Interestingly, the suppression of TLR-mediated responses by helminth antigens has striking similarities with the effects induced by several microbial pathogens that target DC-SIGN 40–42. Recently, significant advances have been made in the identification of pathways downstream of DC-SIGN that result in the modulation of TLR signaling. Lex has been found to modulate, via leukocyte specific protein-1, LPS-induced signaling, by elevating IL10 and reducing IL-12 43. As SEA also alters LPS responses by enhancing IL-10 and reducing IL-12 secretion, it is possible that these signaling pathways play a role in DC conditioning by schistosomes; however, since not all helminth-derived modulatory molecules contain or are glycans, it is reasonable to assume that exploiting CLR to modulate DC function is just one of the ways through which helminths exert their effects on DC activation.

DC modulation through PRR-signaling independent mechanisms

Evidence is emerging that helminth manipulation of DC may also be mediated by mechanisms other than receptor-mediated signaling events, for example, by the enzymatic activities of helminth-derived products. Helminth parasites are known to release a wide variety of enzymatically active products that are thought to play an important role in establishing and maintaining infection by contributing to the degradation of soluble anti-parasitic molecules or the impairment of innate immune cells (reviewed in 44).

With regard to the effects of such molecules on DC, omega-1, a glycosylated RNase secreted by schistosome eggs and present in SEA, was recently found to drive Th2 responses via functional modulation of DC 37, 45. Interestingly, omega-1 could modulate DC function in vitro with characteristics similar to those of SEA, while depletion of omega-1 from SEA abrogated to a large extent its potential to modulate DC function as determined by its capacity to suppress DC LPS-induced IL-12 secretion, expression of maturation markers, and its ability to drive Th2 polarization. In addition, chemical inactivation of omega-1's RNase activity through DEPC treatment led to a significant attenuation of Th2 polarization by omega-1. This suggests that although, as discussed earlier (see DC modulation via PRR signaling), sugars present in SEA may modulate DC function for Th2 priming, the RNase activity present in SEA may also be very important for conditioning DC to drive Th2 responses. Although omega-1 is the first RNase from helminths to be described to induce Th2, other RNases have been linked to Th2 responses. For instance, the allergen Aspf-1, which is an RNase 46, as well as eosinophil-derived neutrotoxin, an RNase from eosinophils, have been found to drive Th2 responses via DC 47. Interference with translation would be in line with reports that several plant-derived enzymes that inactivate ribosomes, so-called ribotoxins, have been identified as allergens, thereby linking Th2 responses with the inhibition of protein synthesis 48, 49.

Furthermore, a number of studies have documented the potent suppressory effects of cystatins, a class of molecules expressed by filarial nematodes, on host immune responses 50–52. This is thought to reflect their capacity to interfere with antigen presentation by DC 53, 54, through blocking the host cysteine protease activity required for the removal of the invariant chain that is necessary for peptide loading onto MHC class II. Thus, rather than promoting Th2 or Treg by DC, cystatins seem to suppress the capacity of DC to prime T-cell responses in general.

Finally, helminth pathogens express cysteine proteases, termed cathepsins, that lead to immune deviation by suppressing Th1 immunity 55. Whether helminth proteases can mediate these effects by targeting DC is at the moment unclear; however, based on the observations that numerous allergens are known to be cysteine proteases 56 and that the cysteine protease Der p 1, one of the major allergens of the house dust mite Dermatophagoides pteronyssinus, has been found to prime monocyte-derived DC for Th2 polarization in a protease dependent manner 57, it is conceivable that such helminth-derived proteases have the potential to favor Th2 polarization through functional modulation of DC.

Taken together, these studies illustrate that DC can become conditioned via PRR signaling dependent (see DC modulation via PRR signaling) and independent mechanisms (this section) by helminth products that include carbohydrates, lipids and proteins or a combination of these, with or without enzymatic activities. A schematic overview of the events leading to DC modulation is shown in Fig. 1, with a summary of helminth-derived components that modulate DC in Table 1. Nonetheless, this wide spectrum of helminth products shares important features, in that the products generally fail to induce conventional DC maturation and suppress activation by pro-inflammatory PAMP, which results in the impairment of Th1 development and a bias of the immune response toward Th2 or Treg. This observation, together with the fact that helminth products are recognized by DC via receptors that also recognize Th1- or Th17-inducing microbial products, suggests that it may not be engagement of the type of receptor itself, but the anti-inflammatory signaling resulting in a muted DC activation profile that sets helminth-derived molecules apart from their microbial counterparts and enables DC to induce Th2- or Treg-polarized immune responses.

Table 1. Helminth-derived antigens/factors that modulate DC function
GroupSpeciesComponentPRRSignaling or mode of actionResulting DC phenotypeT-cell polarizationRefs.
  1. a

    AgB, purified antigen B; ISG, interferon-stimulated gene; IRAK-1, interleukin-1 related accociated kinase-1; ND, not determined; (N)ES, (Nippostrongylus) Excretory/Secretory products; PS, phosphatidylserine; SMAD2/3, SMA/MAD related 2/3; SR-A, class A scavenger receptors.

TrematodesFasciola hepaticaTegumental antigenTLR independent[DOWNWARDS ARROW] NF-κB p65[DOWNWARDS ARROW] IL-12,[DOWNWARDS ARROW]Th136
 Schistosoma mansoniLNFPIIITLR4[UPWARDS ARROW] NF-κB1Low IL-12Th29, 20, 29
  Egg ESCLR?[UPWARDS ARROW] ERK[DOWNWARDS ARROW] IL-12,Th237, 45 unpublished
     [UPWARDS ARROW] IL-10  
  omega-1CLR?Interference with translation?[DOWNWARDS ARROW] IL-12,Th237, 45
     [DOWNWARDS ARROW] Ag presentation  
  Lyso-PS lipidsTLR2ND[DOWNWARDS ARROW] IL-12Treg (Tr1)12
  double stranded RNATLR3STAT-1, ISGIFNαTh113, 15
  0–3 h cercarial ESDC-SIGNNDLow IL-12Th218, 127
CestodesEchinococcus granulosusAgBTLR?[UPWARDS ARROW] IRAK1[DOWNWARDS ARROW] IL-12Th239
NematodesAcanthocheilonema viteaeES-62TLR4[UPWARDS ARROW] ERKLow IL-12Th28, 27, 128
 Ascaris lumbricoidesPS lipidsTLR2[DOWNWARDS ARROW] p38[DOWNWARDS ARROW] IL-12Th211
 Heligmosomoides polygyruscalreticulinSR-A signaling?NDNDTh224
 Nippostrongylus brasiliensisNESNDND[DOWNWARDS ARROW] IL-12 33, 61
AllMultiple helminth speciesCathepsinsCleavage of specific proteins?NDND[DOWNWARDS ARROW]Th155, 129
  CystatinsND[DOWNWARDS ARROW] peptide loading on MHC[DOWNWARDS ARROW]Ag presentation[DOWNWARDS ARROW] T cell activation50–52, 53, 54

Endogenous factors modulating DC function during helminth infection

  1. Top of page
  2. Abstract
  3. Introduction
  4. Modulation of DC function by direct interaction with helminth-derived molecules
  5. Endogenous factors modulating DC function during helminth infection
  6. T-cell polarization by helminth-conditioned DC
  7. Why Th2 and Treg?
  8. Concluding remarks
  9. Acknowledgements
  10. References

Host-derived factors that modulate DC function

Apart from helminth-derived components, several host-derived mediators have been identified that can exert polarizing effects on DC during helminth infection. In this respect, thymic stromal lymphopoietin (TSLP), an IL-7 homolog expressed by several leukocytes and structural cell types, particularly epithelial cells (EC) 58, has been reported to modulate DC function by inducing the expression of MHC class II, costimulatory molecules and the Th2-attracting chemokines TARC and MDC, but not IL-12, resulting in a Th2-polarizing phenotype 59. Recent evidence suggests that TSLP is essential for the generation of protective Th2 immunity against intestinal infection caused by the nematode Trichuris muris60, but not for immunity against H. polygyrus, Nippostrongylus brasiliensis61 or S. mansoni62. Interestingly, while excretory-secretory products (ES) from the latter three worms suppress production of IL-12 by DC, ES from T. muris fails to do so 28, 61. This suggests that helminth-elicited TSLP plays a non-redundant role in priming Th2 responses via DC in infections where DC are not modulated by helminth-derived products, while it is possible to bypass the need for TSLP during infections where DC are able to recognize and respond to helminth-derived factors directly.

Two other cytokines, IL-25 and IL-33, that are expressed by several cell types including EC are critical for protective immunity to intestinal helminths 63, 64. Although these cytokines seem to mainly target T cells for augmentation of Th2 responses 65, there are now also indications that IL-33 can activate DC, as evidenced by increased expression of MHC class II, CD80 and IL-6, but not IL-12, that enables DC to drive Th2 polarization 66. A schematic overview of host factors influencing T-cell polarization by DC during helminth infections is shown in Fig. 2.

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Figure 2. The T-cell-polarizing properties of DC are influenced by both parasite- and host-derived factors during helminth infections. Helminth-derived molecules can directly interact with DC to condition them to drive Th2 or Treg responses. Additionally, innate cells (e.g. mast cells, macrophages and granulocytes), tissue cells (e.g. epithelial cells) and adaptive immune cells (e.g. B cells) secrete several cytokines and other factors in response to helminth infections that can act on DC to shape their immune polarizing properties. Expression of molecules thought to characterize Th2- or Treg-promoting DC, “DC2” and “DCreg,” respectively, are depicted in boxes. AAMacs: Alternatively activated macrophages.

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Apoptosis and nutrition

In contrast to microorganisms, multicellular pathogens like helminths are far more likely to induce serious tissue damage, for instance, due to their capacity to migrate through tissues and cause lesions in the gut wall by feeding. As a consequence, cells in these damaged tissues will be exposed to several forms of cellular stress, which can result in apoptotic cell death. It has been well documented that ingestion of apoptotic bodies or recognition of PS from apoptotic cells by DC 67 suppresses their maturation and IL-12 production 68 and conditions them to drive Treg 69. 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.

Another underexplored mechanism is nutrition. Chronic helminth infections, especially those caused by the species residing in the gastrointestinal tract, can result in malnutrition, primarily as a result of impaired uptake of nutrients 72–74. It is known that undernutrition can result in a compromised function of both the innate and adaptive immune system 75. With respect to DC function, it has recently been shown that in vitro cultured DC derived from children with severe malnutrition produce less pro-inflammatory cytokines, are less mature and have an impaired T-cell-activating capacity compared with DC from well-nourished controls 76. Likewise, in animal models of generalized 77, protein 78 or zinc starvation 79, a consistent defect in the function of APC was observed, as evidenced by a diminished capacity to prime T-cell cytokine production and proliferation. The molecular mechanisms underlying these observations and the extent to which helminth-induced nutritional deficits affect DC function have yet to be elucidated but is an interesting area of research, especially when considering the impact that certain helminth infections have on DC function.

T-cell polarization by helminth-conditioned DC

  1. Top of page
  2. Abstract
  3. Introduction
  4. Modulation of DC function by direct interaction with helminth-derived molecules
  5. Endogenous factors modulating DC function during helminth infection
  6. T-cell polarization by helminth-conditioned DC
  7. Why Th2 and Treg?
  8. Concluding remarks
  9. Acknowledgements
  10. References

Mechanisms behind DC-driven Th2 induction

The requirements for DC to drive Th1 or Th17 polarization in response to viruses, bacteria or fungi have been well established over the past 5 years 80. In contrast, the pathways through which DC prime for Th2 responses in response to helminth antigens are still not fully understood 81. Based on the observations that Th2-polarizing DC exposed to helminth products lack the conventional characteristics of DC maturation and that addition of IL-12 can block the development of a Th2 response following injection with S. mansoni eggs 82, the so-called “default” hypothesis was put forward. The hypothesis states that Th2 responses automatically occur in the absence of Th1-polarizing signals; however, as helminth products are capable of modulating TLR-mediated DC activation leading to a change from Th1 to Th2 11, 28 and as IL-12-deficient mice do not develop a Th2 profile in response to microbial pathogens 83, it is likely that there are active signals involved in Th2 polarization. In recent years, several molecules have been proposed to play an active role in Th2 polarization by helminth-primed DC. For instance, SEA pulsed DC that cannot express CD40 fail to induce Th2 responses both in vitro84 and in vivo85, while DC deficient for CD40 and primed with bacterial components from Propionibacterium acnes are still capable of driving Th1 responses. Furthermore, OX40L has been shown to play an important role in Th2 polarization in vitro by SEA-primed DC 86. Interestingly, TSLP-conditioned DC were also dependent on OX40:OX40L interactions to drive Th2 polarization in vitro87; however, during schistosome 88, as well as gastrointestinal nematode infection 89, OX40L appears to be particularly important for full Th2 development, rather than serving as a direct Th2-polarizing signal. Furthermore, the Notch ligands delta-4 and jagged-2, have been reported to play a role in Th1 and Th2 polarization respectively by DC 90, 91. Yet, although jagged-2 is upregulated in human, as well as murine, DC exposed to SEA 11, 92, the Th2-polarizing capacity of SEA-primed DC deficient for Jagged-2 was unaffected 11, 92, 93. On the other hand, delta-4 expression was found to be suppressed in human DC exposed to lipids derived from schistosome and ascaris worms 11. This, together with the observation that delta-1 and delta-4 not only promote Th1 but also antagonize Th2 polarization 94, suggests that selective inhibition of delta-4 may be a prerequisite for the priming of Th2 development.

In addition to the concept of the induction of independent polarizing signals to drive Th2 responses by helminth products, reduced TCR triggering has been put forward as an alternative model through which DC could prime Th2 polarization during exposure to helminths. In vitro studies have shown that low TCR triggering, as a result of low antigen presentation or low affinity for the peptide/MHCII complex, favors the induction of Th2 responses 95, 96. Bone marrow-derived DC pulsed with a Th2-inducing component of schistosome eggs, omega-1, have an impaired capacity to form T-cell-DC conjugates, and DC stimulated with optimal doses of OVA in the presence of omega-1 displayed a lower T-cell activation profile similar to that seen in DC pulsed with low doses of OVA alone 45. This suggests that omega-1 interferes with antigen presentation and proper TCR triggering, which may consequently lead to the induction of Th2 responses. Maybe this extends to Th2 polarization by helminths in general since, on the one hand, receptor-mediated DC modulation may, via signaling-dependent mechanisms, suppress IL-12 production and promote the expression of Th2-polarizing factors; yet, on the other hand, signaling-independent pathways such as enzymatic activity (RNases and proteases) or direct interference with antigen presentation (cystatins) may lead to reduced antigen presentation to T cells and thereby reduced TCR triggering (Fig. 1).

A great deal of what we know about Th2 polarization by DC in response to helminths has been based on in vitro culture systems that ignore the complexity of the in vivo immune response. In light of this, it is of course possible that tissue factors provide the polarizing signals that licence DC to prime Th2 responses. For instance, IL-4 derived from innate cells such as basophils can serve as a Th2-polarizing signal 97. In fact, recent findings in a T. muris model demonstrate that in some settings, basophils may even overtake the function of DC by functioning as professional APC 98. This illustrates that we may need to look further than DC to fully understand the mechanisms behind Th2 polarization by helminths.

Mechanisms behind DC-driven Treg induction

It is well documented that helminth infections lead to the induction and expansion of Treg (reviewed in 2, 3). 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 helminth-derived products, host-derived cytokines such as IL-10 and TGF-β, or apoptotic cells generated during helminth infections are likely to play an important role in DC-driven Treg induction. Treg induction by IL-10-conditioned DC have been linked to expression of immunologlobulin like transcripts 3 and 4 (ILT-3, -4) 99, programmed death ligand 1 (PDL-1) 100 and/or the tryptophan-depleting enzyme indoleamine 2,3-dioxygenase (IDO) 101. The finding that Schistosoma mansoni worms can induce anergic T cells via selective up-regulation of PDL-1 on APC 102 suggests that at least one of these pathways plays a role in schistosome-induced tolerogenic responses. In addition, IL-10 and TGF-β from DC may be acting on the T-cell-polarization process directly to prime Treg differentiation 103–105. Apart from de novo induction of Treg by DC, helminth infections have also been demonstrated to lead to expansion of pre-existing naturally occurring Treg 106, 107. DC are known for their capacity to mediate this expansion in vitro, and are therefore likely to contribute to this in vivo (reviewed in 108), even though the requirements for this process are at the moment unclear.

Why Th2 and Treg?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Modulation of DC function by direct interaction with helminth-derived molecules
  5. Endogenous factors modulating DC function during helminth infection
  6. T-cell polarization by helminth-conditioned DC
  7. Why Th2 and Treg?
  8. Concluding remarks
  9. Acknowledgements
  10. References

The origin of, and need for, Th2 responses

The fact that helminth infections consistently result in the generation of type 2 immune responses has led to the concept that this type of immune response has been propagated by the host to counteract these infections. But what is the evidence for this? The observation that mice deficient for the canonical Th2 effector cytokines IL-4 and IL-13, IL-4R-α or its downstream signal transducer STAT6 fail to clear the intestinal nematode parasites N. brasiliensis, Trichinella spiralis and T. muris supports the view that Th2 responses are crucial in providing immunity against these helminths; however, the protective effects of Th2 responses during infections caused by helminths that have found their niche at sites other than the gastrointestinal tract are far less clear cut. For instance, the Th2 response generated during schistosome infection, mainly in response to the eggs, is insufficient to expel the worms. Instead, the Th2 response causes the formation of type 2 granulomas around the eggs once they become trapped in the liver (reviewed in 109). It is thought that this encapsulation of parasite eggs is important for constraining inflammation potentially caused by the eggs. This is illustrated by the fact that S. mansoni-infected mice lacking IL-4 and/or IL-13 display an uncontrolled Th1-biased response that results in hepatocyte damage and intestinal pathology 110, 111.

These observations suggest that Th2 immune responses may not only be generated to kill the parasites, but have also evolved to prevent the excessive tissue damage that is inflicted by helminths. Therefore, it is not surprising that mechanisms to repair damaged host tissues would be an integral part of an appropriate immune response against helminths 112. This concept of tissue repair is in line with the observation that alternatively activated macrophages, which play a crucial role in type 2-associated processes such as fibrosis 113, are highly reminiscent of the macrophages that are required for wound healing and which are found in lesions caused by non-infectious injuries 114. On this basis, one could hypothesize that not only are tissue repair mechanisms part of the Th2 response seen during helminth infections, but that tissue damage and cellular stress inflicted by the parasites are actually the triggers for the induction of type 2 responses. The fact that the major hepatotoxic component from schistosome eggs, omega-1, has now been identified as the a major Th2-inducing factor secreted by those eggs 37, 115 is in agreement with this hypothesis. Likewise, promotion of oxidative stress in DC has been associated with the induction of type 2 inflammation during allergic responses 116. Lastly, the recent findings that TLSP is not only elicited from EC during helminth infections but also following trauma and injury in the lungs is also consistent with a direct link between tissue damage/cell stress and the induction of Th2 responses during helminth infections 117.

Although type 2 immune responses seem to contribute to the restriction of tissue damage during helminth infections, when too strong, they may aggrevate pathology due to excessive tissue fibrosis. Therefore, restraining excessive inflammatory Th2 responses during helminth infections is imperative for the prevention of potentially harmful inflammation and the survival of the host. Modulation of the intrinsic characteristics of the Th2 response due to host homeostatic mechanisms during helminth infections (classified as a so-called “modified” Th2 response) has been implicated in this process and the activation of regulatory responses (see The origin of, and need for, Treg responses) 2.

Taken together, these data lead to the notion that type 2 responses are generally beneficial for the host by either mediating worm expulsion or repairing and preventing tissue damage caused by the parasite provided that this response is well controlled 109. Furthermore, there may be support for the view that the immune system has evolved to induce type 2 immunity in response not only to the parasites themselves but also to the tissue damage caused by the parasites. Interestingly, this concept may also shed new light on the, so far, unsuccessful search for true Th2-priming PRR that specifically recognize helminth components, since sensing of stress signals by tissue damage, e.g. by DAMP 118, may provide an alternative mechanism through which APC could become conditioned for induction of Th2 responses during helminth infections; however, whether or not type 2 immune responses to tissue damage are triggered may, for a large part, depend on the type of tissues or cells affected and/or the type of stress and tissue damage that is inflicted. For instance, the damage-driven models of colitis and multiple sclerosis are characterized by Th1/17 biased autoimmune responses 119, 120. Furthermore, it should be noted that the processes involved in wound healing and type 2 immune responses occurring during helminth infections only overlap partially, as exemplified by the fact that anti-helminth effector mechanisms such as those driven by IgE and eosinophils are not normally involved in tissue repair. These latter observations illustrate that apart from this concept of sensing of tissue damage in the context of helminth infections, additional signals provided by helminth-derived products through direct interactions with PRR on innate cells such as DC are still of critical importance for the development of full type 2 immunity against helminths.

The origin of, and need for, Treg responses

Despite vigorous induction of Th2 immune responses by the host, helminth infections, including the ones caused by intestinal parasites, generally result in persistent infections. Although this may, in part, arise from the intrinsic limitations of Th2 responses to confer immunity against certain helminth species, it is also thought to reflect the capacity of helminths to actively promote the induction of regulatory immune responses. Normally, during non-infectious conditions, these regulatory responses are an integral part of the host's immune system that keeps detrimental immune responses against self- or innocuous antigens in check. To increase the chances of survival, parasitic worms have evolved to exploit this Achilles' heel of the immune system by promoting the induction and expansion of Treg responses that result in downregulation of Th2 effector responses against the parasites (reviewed in 2, 3). The importance of this mechanism for the survival of the parasite is exemplified by the fact that, after depletion of Treg or neutralization of their suppressor molecules, Th2 immunity and protection against the infection can be restored 121–123. Although Treg responses are beneficial to the parasite, the promotion of this regulatory arm is thought to be important for the host as well, since in several helminth models IL-10-deficient mice display severe pathology and increased mortality as a result of an overt inflammatory response to the parasitic infection 124–126. Thus, it appears that regulatory responses can benefit both host and parasite. Therefore, an immune profile with well controlled or ‘modified’ Th2 plus a Treg component may be the best compromise for (i) the host by preventing excessive inflammation and pathology and (ii) the parasite as the parasite can survive long enough to be successfully transmitted to the next host (Fig. 3).

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Figure 3. The balance between Th2 and Treg responses will determine the survival chances of both the host and the parasite. (A) If a Th2 response during a chronic helminth infection is insufficiently counterbalanced by a regulatory response, the immune pathology by Th2 inflammation will be detrimental for both the host and parasite. (B) Conversely, a too strong regulatory component will enhance parasite burden and its associated pathology, as a result of suppressed anti-helminth Th2 responses. (C) Therefore, during co-evolution of parasite and host, it is likely that a balance between type 2 and regulatory responses has evolved that benefits both helminth and host, as this allows them to co-exist without too severe pathology. Bold, normal and dashed lines represent strong, normal and weak activation (arrow-head) or suppression (flat arrow-head), respectively.

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Concluding remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. Modulation of DC function by direct interaction with helminth-derived molecules
  5. Endogenous factors modulating DC function during helminth infection
  6. T-cell polarization by helminth-conditioned DC
  7. Why Th2 and Treg?
  8. Concluding remarks
  9. Acknowledgements
  10. References

A balanced Th2 and Treg response is ultimately of critical importance for the survival of both the parasite and the host. It is therefore not surprising from a host's point of view that DC, as the orchestrators of immune responses, are well equipped to efficiently sense helminth infections in a variety of ways. This may involve not only direct interactions with helminth-derived products but also via factors released by the host in response to infections. In addition, sensing of stress signals that are inflicted by the worms may represent a so far unappreciated pathway through which DC acquire a Th2- or Treg-polarizing phenotype. Since during natural infection DC are likely to be exposed to multiple immune-polarizing or -modulating signals, it is probable that integration of these signals by DC will induce a fine-tuned Th response that may not only include “classical” Th2 or Treg responses, but also include intermediate Th cell phenotypes. While we are only beginning to appreciate the mechanisms underlying these phenomena, it is evident that a better understanding of the interplay between host and parasite at the level of DC will be imperative for unraveling the mechanisms underlying other Th2-mediated disorders, such as allergic diseases.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Modulation of DC function by direct interaction with helminth-derived molecules
  5. Endogenous factors modulating DC function during helminth infection
  6. T-cell polarization by helminth-conditioned DC
  7. Why Th2 and Treg?
  8. Concluding remarks
  9. Acknowledgements
  10. References

This work was supported by the Netherlands Foundation for the Advancement of Tropical Research (WOTRO), project number W93-385 20.077, and the Dutch Organization for Scientific Research (NWO grant No ZONMW 912-03-048, ZONMW-VENI 016.066.093).

Conflict of interest: The authors declare no financial or commercial conflict of interest.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Modulation of DC function by direct interaction with helminth-derived molecules
  5. Endogenous factors modulating DC function during helminth infection
  6. T-cell polarization by helminth-conditioned DC
  7. Why Th2 and Treg?
  8. Concluding remarks
  9. Acknowledgements
  10. References
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