Invited review Intestinal nematode parasites, cytokines and effector mechanisms

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Abstract

Laboratory models of intestinal nematode infection have played an important role in developing our understanding of the immune mechanisms that operate against infectious agents. The type of helper T cell response that develops following infection with intestinal nematode parasites is critical to the outcome of infection. The early events that mediate polarisation of the helper T cell subsets towards either Th1 or Th2 during intestinal nematode infection are not well characterised, but it is likely that multiple factors influence the induction of a Th1 or Th2 type response, just as multiple effector mechanisms are involved in worm expulsion. Costimulatory molecules have been shown to be important in driving T helper cell development down a specific pathway as has the immediate cytokine environment during T cell activation. If helper T cells of the Th2 type gain ascendancy then a protective immune response ensues, mediated by Th2 type cytokines and the effector mechanisms they control. In contrast, if an inappropriate Th1 type response predominates the ability to expel infection is compromised. Equally important is the observation that multiple potential effector mechanisms are stimulated by nematode infection, with a unique combination operating against the parasite depending on nematode species and its life cycle stage. Despite the close association between intestinal nematode infection and the generation of eosinophilia, mastocytosis and IgE it has been difficult to consistently demonstrate a role for these effector cells\molecules in resistance to nematode parasites, although mast cells are clearly important in some cases. It therefore seems that, in general, less classical Th2 controlled effector mechanisms, which remain poorly defined, are probably important in resistance to nematode parasites. Thus, our understanding of both the induction and effector phases remains incomplete and will remain an intense area of interest in the coming years.

Introduction

Intestinal nematodes are some of the most prevalent infections of humans. Estimates of the global incidence of the major species, Ascaris lumbricoides, hookworm (Necator americanus and Ancylostoma duodenale) and Trichuris trichiura suggest that over 1000 million people are infected with each of these parasite species [1]. Infections tend to be chronic, have high reinfection rates and are typically overdispersed with intense infections confined to the minority of the population 2, 3. Such intense infections are associated with clinical disease but moderate levels of infection are also pathogenic, having important developmental consequences, particularly for children [4].

Despite the chronic nature of many of these human nematode infections, immunoepidemiological studies provide compelling evidence for the existence of protective immunity in the field [5]. In such studies behavioural, nutritional and environmental factors represent multiple variables that compound to make field data complex and hard to interpret. The development of well defined laboratory models of human infection has hence made a significant contribution to our understanding of immunity to infection. Indeed laboratory models have contributed to our understanding of immunity to infection at three levels:

  • 1.

    1. the types of T cell responses which control\ regulate the effector response.

  • 2.

    2. the events involved in initiating a particular type of T cell response.

  • 3.

    3. the effector mechanisms responsible for worm expulsion.

Recent studies have concentrated on four main species of intestinal nematode parasites, Nippostrongylus brasiliensis, Trichinella spiralis, Heligmosomoides polygyrus and Trichuris muris in the mouse. Each parasite has its own unique life cycle characteristics: N. brasiliensis and T. spiralis both have tissue migratory larval stages; adult stages of N. brasiliensis and H. polygyrus live in the gut lumen whilst T. muris induces syncitium formation and lives completely or partially within the intestinal epithelial cells according to the stage of the parasite present, and T. muris occupies a niche within the large intestine whilst the other three parasites are small intestinal dwelling. Not surprisingly, therefore, each parasite provokes slightly different immune responses in the host and requires a different set of effector mechanisms to bring about expulsion. Important differences also exist in the ability of the mouse host to expel a primary infection with each of the four nematodes. Thus, primary infections with T. spiralis and N. brasiliensis are expelled from the mouse within weeks 6, 7, 8whereas the ability to expel a primary T. muris infection is dependent on the strain of mouse infected [9]. In contrast primary infections with H. polygyrus tend to be chronic, although challenge infections are readily expelled 10, 11. Data on immunity to H. polygyrus infection therefore are often based on the responses seen during a secondary infection.

A central role for CD4+ helper T cells in resistance to infection has been demonstrated for all four species by adoptive transfers and\or in vivo depletions of CD4+ cells 12, 13, 14, 15. The discovery that CD4+ T cells can be divided into at least two polarised helper T cell subsets, Th1 and Th2, in both humans and mice 16, 17provided a basis for understanding the underlying cell regulatory mechanisms controlling resistance to infection. Th1 and Th2 cell subsets are defined by the set of cytokines they secrete. Thus Th1 type cells produce interferon-gamma (IFN-γ), lymphotoxin, and interleukin-2 (IL-2) whilst Th2 type cells secrete IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13. A naive T cell can differentiate into either a Th1 or Th2 type cell, passing through an intermediate stage where it has an unrestricted cytokine profile 18, 19, 20. The differentiation pathway towards either Th1 or Th2 is influenced by a number of factors, the most potent of which seems to be the immediate cytokine environment a T cell experiences at the time of antigen presentation 21, 22. Thus, IL-12 promotes the development of Th1 type cells whilst Th2 type cells develop in the presence of IL-4 23, 24, 25, 26. The interaction between each cytokine and its receptor leads to the activation of signalling molecules including signal transducer and activator of transcription (STAT) proteins. Two STAT proteins have been shown to be involved in helper T cell subset development: STAT-4 is activated by IL-12 and is important in the development of Th1 cells 27, 28, 29whilst IL-4 activates STAT-6 in Th2 cells 30, 31. Thus STAT-4 and STAT-6 knockout mice have reduced abilities to mount Th1 and Th2 type responses respectively 32, 33. Once an immune response starts to polarise it becomes progressively more polarised due to the cross-regulatory effects of each subset’s signature cytokines 34, 35.

Analyses of cytokine mRNA expression during intestinal nematode infection or cytokines secreted after in vitro restimulation of draining lymph node cells reveal a dominant Th2 type response in mice resistant to intestinal nematode infection 36, 37, 38, 39, 40, 41. This is in contrast to the dominant Th1 type responses triggered by intracellular pathogens such as Leishmania major during resolution of infection [42].

The clearest evidence for the importance of Th2 cytokines, and specifically the Th2 cytokine IL-4, in resistance to infection comes from the H. polygyrus and T. muris models. The ability of mice to expel a challenge infection with H. polygyrus can be blocked for at least 17 days post challenge using mAbs against IL-4 or its receptor, which blocks the IL-13 receptor as well as the IL-4 receptor [43]. Control mice expel their challenge infection well within this time period. Likewise, host protective immunity to a primary T. muris can be abrogated using mAbs against the IL-4 receptor [44]. This treatment results in the establishment of a chronic infection in a normally resistant strain of mouse and is accompanied by an upregulation of Th1 type responses (IFN-γ production and IgG2a) and a downregulation of responses typically associated with Th2 cells such as IgE and IgG1 production, eosinophilia and mastocytosis. Data from gene-targeted mice support these in vivo ablation studies. Thus, IL-4 knockout mice, which lack a functional IL-4 gene, are susceptible to a primary T. muris infection and are unable to mount a protective immune response to H. polygyrus 40, 45. A central role for IL-4 in the development of resistance to these two intestinal nematode parasites has been further demonstrated by administering IL-4 as a complex with a neutralising anti-IL-4 mAb to mice with chronic infections. IL-4 administered as an IL-4 complex has an extended half life in vivo [46]and facilitates expulsion of both T. muris and H. polygyrus 44, 47. IL-4 also appears to be important in the development of resistance to a primary infection with T. spriralis, with mice treated with anti-IL4 receptor mAb exhibiting a prolonged adult infection and having higher muscle larval burdens [40].

The role of IL-4 in the development of protective immunity to a primary infection with N. brasiliensis is more complex. In dissecting out the involvement of IL-4 in resistance to this parasite, an important and probably dominant role of another Th2 type cytokine, IL-13, has been revealed. Thus, IL-4 knockout mice expel N. brasiliensis normally as do anti-IL-4 receptor mAb treated mice 41, 48. As mentioned above, this antibody blocks both the IL-4 and IL-13 receptor, presumably via blocking the common IL-4 receptor alpha chain. These observations initially suggest that IL-13 is not responsible for the observed IL-4 independent worm expulsion. However, a series of recent experiments have shown that IL-4 receptor alpha knockout mice, IL-4 knockout mice treated with the anti-IL-4 receptor mAb and STAT6 knockout mice all fail to expel a primary N. brasiliensis infection [49]. Only IL-4 and IL-13 are currently known to cause STAT6 activation by the IL-4 receptor alpha chain, so taken together these data suggest that IL-13 can indeed mediate resistance to infection in the absence of IL-4 and perhaps anti-IL-4 receptor mAb treatment does not lead to a complete blocking of the IL-13 receptor in immunocompetent mice. Indeed, treatment of N. brasiliensis infected immunocompetent mice with a soluble IL-13 receptor alpha 2-human IgGFc fusion protein (sIL-13Rα 2-Fc) dramatically inhibits expulsion of N. brasiliensis. Fecund adult worms are still present 16 days p.i. whereas control mice harbour no worms at this time point. Importantly, IL-4 knockout mice treated in a similar manner with the sIL-13Rα 2-Fc, harbour higher numbers of more fecund parasites than the immunocompetent sIL-13Rα 2-Fc-treated mice. These data suggest that both IL-4 and IL-13 contribute to the expulsion of N. brasiliensis, operating through an IL-4 receptor alpha-dependent, STAT6 dependent mechanism, with IL-13 probably being quantitatively the more important cytokine. Interestingly, although STAT6 knockout mice are unable to expel a primary N. brasiliensis, they do mount very strong anti-parasite IgG1 and IgG2 responses compared with wild type mice and develop a profound intestinal mastocytosis, clearly implying that antibody and mast cells are not sufficient to expel N. brasiliensis [49], (see below).

A role for IL-4 in controlling a normally redundant immune mechanism operating against N. brasiliensis has also been revealed by studies carried out in anti-CD4 treated mice and SCID mice. Thus, IL-4 complexes administered to these CD4+ deficient mouse models are sufficient to cause expulsion of chronic N. brasiliensis infections[47].

IL-13 is also thought to be important in resistance to T. muris. During the generation of a protective primary immune response to this parasite, IL-13 is produced in large amounts. Recent data have shown that mice with a targeted disruption in the IL-13 gene are fully susceptible to T. muris infection unlike their wild type controls [45], demonstrating the importance of this cytokine in the development of protective immunity. A role for another Th2 type cytokine, IL-9, in resistance to both primary T. spiralis and T. muris infections is also evident. Again, this cytokine is produced in very high amounts by resistant strains of mice p.i. and has been shown to increase resistance to these two parasites ([50], Faulkner H, Renauld J-C, Van Snick J and Grencis RK, unpublished). In the case of T. spiralis, IL-9 is probably acting via its role in enhancing Th2 type responses and, specifically, mastocytosis (see below). However, although IL-9 seems to promote the loss of T. muris, the effector mechanisms operating are unknown. Some of the differences and similarities in the protective immune responses which develop during infection of mice with each of the four species of intestinal nematode parasite are summarised in Table 1..3. Th1 type responses promote susceptibility to infection Arguably the best model for illustrating the deleterious effects that Th1 cytokines have on host protective immunity to intestinal nematode infection is T. muris in the mouse. Susceptible strains of mouse respond to a primary T. muris infection by mounting an immune response characterised by high levels of IFN-γ and parasite-specific IgG2a, both hallmarks of a Th1 type response. These mice go on to harbour long term chronic infections and are unable to expel the parasite 36, 37. If, however, susceptible strains are treated with anti-IFN-γ mAbs during the early larval stages of infection, they are able to expel the parasite and mount a Th2 type response [44]. Likewise treatment of susceptible mice with anti-IL-12 mAbs early in infection promotes resistance [Bancroft AJ pers comm]. Conversely, treatment of normally resistant strains of mouse with IL-12 allows the establishment of a chronic infection, with IL-12 having its effects via the induction of IFN-γ [51]. IL-12 has also been shown to prolong infection with N. brasiliensis and, again, the IL-12 effects are dependent on IFN-γ [52].

The Th2 controlled effector mechanisms which limit intestinal nematode infection in most cases, are unidentified. The Th2 type responses observed during intestinal nematode infection are accompanied by an elevation in a number of parameters including eosinophilia, intestinal mastocytosis and IgE. Although classical hallmarks of intestinal helminth infection, a direct role for these effector cells\antibodies in resistance to infection has been difficult to demonstrate. However, through selective ablation studies and the use of gene targeted mice, it has been possible to address the role of specific components of the immune response observed in resistance to infection.

A significant eosinophilia is observed during intestinal nematode infection and there is a marked increase in levels of IL-5, the Th2 type cytokine responsible for the generation of eosinophils. Despite this, a protective role for eosinophils has not been identified. Thus, treatment of mice with anti-IL-5 mAbs to ablate eosinophilia does not prevent the expulsion N. brasiliensis [53], T. spiralis [54], T. muris (Betts CJ, Else KJ, unpublished), or H. polygyrus [43], strongly suggesting that eosinophils are not a major effector mechanism against helminths that reside in the gut. In contrast, there is some evidence for an eosinophil mediated protective immune response operating against the migratory tissue dwelling larval stages of two other nematodes, Angiostrongylus cantonensis [55], and Strongyloides venezuelensis [56].

A prominent mastocytosis is observed during gut nematode infections and is controlled by a variety of Th2 type cytokines, including IL-3, IL-4, IL-9, IL-10 and the growth factor stem cell factor 57, 58, 59, 60, 61, 62, 63, 64, 65. Treatment of mice with anti-IL-3 and anti-IL-4 mAb results in an 85% decrease in the mastocytosis observed during a primary N. brasiliensis infection but does not prevent worm expulsion [48]. Likewise W\Wv mice, which have a defect in the stem cell factor receptor c-kit, and are thus deficient in intestinal mast cells, are still able to expel a N. brasiliensis infection [66]. In addition, and as mentioned earlier, STAT6 knockout mice develop a strong intestinal mastocytosis during N. brasiliensis infection and yet are unable to expel this parasite [49]. The mast cell also seems to be non-essential in resistance to a primary infection with T. muris. Here treatment of mice with anti-IL-3 mAbs to partially depress the intestinal mastocytosis, or with antibodies to the stem cell factor receptor, which abrogates mast cell development, fails to alter the course of expulsion in resistant strains of mice (Betts CJ, Else KJ, unpublished).

In contrast there is compelling evidence that the mast cell plays a major role in resistance to a primary infection with T. spiralis. Infection of mice with T. spiralis provokes a severe inflammatory response in the small intestine with the mast cell representing a major component of this inflammation. Measurements of mucosal mast cell specific proteases during infection have demonstrated that the mast cells are functionally active [67]. Early studies detected a delay in expulsion of T. spiralis from W\Wv mice [68]. Subsequently it was demonstrated that antibodies to stem cell factor or its receptor, c-kit, inhibited the expulsion of a primary T. spiralis infection and abrogated the mast cell response [69]. Evidence for a mast cell mediated effector mechanism operating against T. spiralis is also provided by studies performed in IL-9 transgenic mice. These mice, which constitutively overexpress IL-9, have heightened Th2 type responses in general and display extremely fast expulsion kinetics. However, treatment of these mice with anti-c-kit mAbs dramatically delays worm expulsion, accompanied by a severely depressed intestinal mastocytosis [50].

The mast cell may also play a role in resistance to H. polygyrus. A primary infection with this parasite is chronic in most strains of mouse and, in general, a mast cell response is absent. Some strains however do eventually exhibit a protective immune response to a primary infection, and expel the parasite [39]. In situations where worm expulsion is observed a mast cell response does begin to develop and, in contrast to strains of mouse which cannot eliminate their worm burdens, these resistant mice are able to maintain elevated levels of IL-3 and IL-9 [39]. Thus it would appear that there is an immunomodulatory effect of H. polygyrus resulting in a selective down regulation of some Th2 associated cytokines and the prevention of an appropriate effector mechanism.

In situations where mast cells appear to play an important role in resistance to infection, the exact mechanism by which they do so has not been identified. It is likely that they contribute to a non-specific inflammatory response within the gut through the secretion of inflammatory mediators such as proteases and leukotrienes. Leukotrienes and mast cell proteases are known to be produced during intestinal helminth infection 67, 70, 71and mast cell protease production in the rat has been shown to correlate with an increased permeability of the gut epithelium [72]. Such changes will contribute to the development of an environment that is potentially detrimental to worm survival.

Mast cell activation during parasitic infection represents another relatively undefined area. Classically, mast cell activation involves the binding of IgE to the high affinity IgE receptors (FcεRI) on mast cells, and certainly an elevation in serum IgE is observed during infection. However, much of this IgE is non-specific and may even serve to promote worm survival by blocking the IgE receptors on mast cells thus preventing specific IgE from binding [73]. In addition, it is clear from experiments using mice with a disruption in the γ chain of the Fc receptor (FcγR knockout mice), which hence lack FcεRI, that mast cell activation can occur independently of IgE. Thus, infection of FcγR knockout mice with T. spiralis or T. muris provokes an intestinal mast cell response accompanied by mast cell protease release and worm expulsion [Grencis RK, Betts CJ, Ravetch J and Else KJ, unpublished].

A Th2 controlled antibody isotype as an effector molecule in resistance to infection has been a favoured hypothesis over the years, based on the ability to transfer protective immunity with large volumes of immune serum given early during infection [74]. As high levels of parasite-specific antibodies are not usually generated this early p.i., if antibody does play a role it may contribute more to resistance to secondary rather than primary infections. Intestinal nematode infection is accompanied typically by elevations in IgG1 and IgE, with both these isotypes under the control of Th2 type cytokines. The passive transfer of purified IgG1 has implicated this isotype in resistance to H. polygyrus [75]and there is evidence from studies using T. spiralis in the rat that IgE may be important. Here rapid expulsion can be transferred with purified IgE antibody and suppression of the IgE response results in increased muscle larvae burdens 76, 77, 78. However, there are probably important differences in the effector mechanisms operating in the rat compared to the mouse. Transfer of immunity to a primary T. spiralis infection in the mouse using immune sera from infected mice has given equivocal results 79, 80. In contrast, high levels of immunity can be achieved using sera from vaccinated mice 81, 82. This suggests that vaccination results in antibody responses quantitatively or qualitatively different from those generated by infection and that the effector responses to T. spiralis following infection and vaccination are different. Despite these studies, an essential role for antibody in resistance to gut parasites has not been demonstrated. This is typified by studies conducted with T. muris. Here passive transfer studies have again shown that antibody can enhance resistance to infection [83]. However the adoptive transfer of highly pure immune CD4+ T cells to SCID mice, which lack functional B or T cells, very readily protects these mice from a primary T. muris infection in the complete absence of an antibody response [84]. In addition some mice, such as the IL-9 transgenic animals, are able to mediate expulsion of T. muris very rapidly in the absence of any detectable parasite specific antibodies (Faulkner H, Renauld J-C, Van Snick J, Grencis RK, unpublished). As mentioned above FcγR knockout mice are resistant to T. muris infection; therefore a classical antibody\cell interaction is not necessary for worm expulsion. A non-essential role for antibody in protective immune responses is also seen in the context of N. brasiliensis infection. Here, STAT6 knockout mice generate strong anti-parasite antibody responses yet cannot expel N. brasiliensis [49]and mice treated with anti-IgM produce little antibody but retain their ability to expel this parasite [85]. In contrast, μ chain deficient mice, which lack B cells, develop more severe secondary H. polygyrus infections than control animals. However this may be related to the importance of the B cell as an antigen presenting cell rather than reflecting a lack of antibody [40]. Thus there are very few data to indicate that antibody represents a principal effector mechanism in resistance to intestinal nematodes, although relatively little attention has been paid to local as opposed to peripheral antibody production in the context of infection. Thus, antibodies secreted at mucosal surfaces may yet prove to be important in protective immunity to gut dwelling helminths.

As mentioned in the previous section, CD4+ T cells can transfer immunity to SCID mice in the absence of antibody and with no other potential classical effector mechanism (mastocytosis, eosinophilia) correlating with resistance status. This raises the question as to how the CD4+ T cells are mediating immunity. One possibilty is that a Th2 cytokine, and specifically IL-4, could act as an effector molecule as opposed to simply directing and amplifying the helper T cell response towards Th2. Certainly there are strong data to suggest that IL-4 can mediate protection in this manner against at least some stages of some intestinal helminths. Thus, if mice with established H. polygyrus infections are treated with IL-4 in the form of a complex with a neutralising anti-IL-4 mAb, as outlined earlier, a decrease in worm fecundity and worm numbers is observed [47]. These anti-parasite effects are accompanied by changes in gastrointestinal physiology including increased fluid secretion and smooth muscle contractibility 40, 47. The effects of exogenous IL-4 treatment are only apparent against adult stages of the parasite and seem to involve the mast cell as they are not observed in IL-4 complex treated W\Wv mice. IL-4 complex treatment of N. brasiliensis-infected SCID mice is also anti-parasitic. Again the effects are directed against the adult stages of the parasite, but in this model cure is more complete and the mast cell is not involved [47]. IL-4 complex treatment fails to bring about expulsion of N. brasiliensis in STAT6 knockout mice; therefore it is unlikely that IL-4 is operating via a direct action on the worm itself [40]. Indeed, it is felt likely that the mechanism by which IL-4 is promoting adult worm expulsion is by inhibiting feeding through the observed changes in intestinal physiology [40]. In the context of T. muris infection, IL-4 complex treatment brings about a decrease in the adult worm burdens of SCID mice but, in common with the H. polygyrus and N. brasiliensis models, has no effect against larval parasites [Else, Finkelman and Betts, unpublished]. This raises the question of the importance of this sort of effector mechanism in vivo in a normally resistant host, where worm loss occurs during the larval stages of parasite development. Certainly in the CD4+ to SCID adoptive transfer model, worm loss is complete by the L3 stage. In vivo tracking studies have shown that these CD4+ T cells home to the gut epithelium of infected mice and peak in numbers at the time of worm expulsion, raising the possibility of some form of CD4+ mediated cytotoxicity operating in resistance to this intracellular helminth parasite [Else and Betts, unpublished].

Many intestinal nematode infections induce a goblet cell hyperplasia and an increase in mucin production, with these changes thought to be at least in part under the control of a CD4+ Th2 type response 86, 87, [Khan and Grencis, pers comm]. Although a feature of most intestinal nematode infections, the role of the goblet cell in the protective immune response has not received much attention. Possibly the strongest data for a role of the goblet cell in parasite expulsion are provided by the N. brasiliensis model in the rat, during both primary and challenge infections. Here, increases in goblet cell numbers and the quantity and quality of mucus secreted have been demonstrated 88, 89, 90. Goblet cell hyperplasias are also prominent during primary infections of mice with T. spiralis 86, 87and T. muris [Khan and Grencis, pers comm] with a correlation between worm expulsion and peak mucin production observed for the latter parasite. Table 2 summarises the possible involvement of candidate effector cells and molecules in resistance to T. spiralis, T. muris, H. polygyrus and N. brasiliensis.

The ability to divide helper T cells into defined subsets according to their cytokine profiles has contributed significantly to our understanding of the underlying cell regulatory mechanisms that control resistance and susceptibility to intestinal nematode infection. It is apparent that resistance to this type of pathogen requires the development of a dominant Th2 type response with a Th1 dominated response being inappropriate for the generation of protective immunity. Our knowledge of the actual Th2 controlled effector mechanisms that culminate in worm expulsion is less complete and varies according to the parasite species and developmental stage. Likewise we are only just beginning to appreciate the developmental regulation of Th1 and Th2 type cells from naive precursors during infection.

One of the critical influences in helper T cell subset polarisation has been shown to be the immediate cytokine environment at the time of antigen presentation, with IL-12 promoting differentiation towards Th1 cells and IL-4 promoting the development of Th2 type cells 23, 24, 25, 26. Both macrophages and dendritic cells are major IL-12 producing cells whilst the cellular source of early IL-4 production remains uncertain. One possible candidate is the NK1.1+ CD4+ αβ T cell. Although there is little direct evidence implicating NK1.1+ CD4+ αβ T cells as the early source of IL-4 during intestinal nematode infections, they are known to produce IL-4 very quickly upon stimulation through CD3 [91]. These cells are thought to be stimulated by antigen presented by CD1 molecules, rather than conventional MHC molecules [92]. CD1 molecules are expressed at high levels on intestinal epithelium and thus are good candidates for presenting antigen from intestinal dwelling parasites [93].

The type of antigen presenting cell (APC) involved has also been shown to be important, with antigen presented by macrophages favouring Th1 development whilst antigen presentation by B cells appears to induce Th2 type responses [94]. Related to this, the costimulatory interactions which occur between APC and T cell are also thought to be involved in helper T cell subset polarisation, with attention centring on the interaction between B7 molecules on APCs and their counter receptors CD28 and CTLA4 on T cells [95]. It is in this area that most work on the induction of helper T cell subset during intestinal nematode infection has been conducted. Initial studies involved the use of mice with experimental allergic encephalomyelitis 96, 97. Here it was demonstrated, via the manipulation of the interactions between the B7 molecules on APCs and their ligands (CD28\CTLA4) on T cells, that stimulation via B7-1 promoted a Th1 type response whilst stimulation through B7-2 resulted in a Th2 polarisation. In the context of H. polygyrus infection, there is little evidence for the differential signalling of Th1 and Th2 type cells through B7-1 and B7-2. Administration of CTLA4Ig (a chimeric fusion protein which binds to and blocks B7 molecules) to H. polygyrus infected mice inhibits the development of a Th2 type response [98]and recent work, using anti-B7-1 and anti-B7-2 mAbs, has demonstrated that this Th2 type response is only blocked when mice are treated with both antibodies [99]. Thus, either B7-1 or B7-2 is sufficient to stimulate a Th2 response to H. polygyrus. In contrast, antibodies directed against B7-2 alone prevent the generation of a Th2 type response in mice normally resistant to T. muris and hence allows the establishment of a chronic, Th1 dominated infection [Else KJ, Bancroft AJ, Abe R and Grencis RK, unpublished].

Other factors have also been implicated in determining helper T cell subset differentiation. In T. muris infection, antigen load has been shown to be important with a low level infection in a normally resistant, Th2 dominated host promoting the development of a Th1 type response and susceptibility to infection [100]. Non-MHC linked genetic factors are also clearly important, although they have not been studied in any great detail for intestinal nematode parasites. It has been suggested that BALB\c mice develop a disease exacerbating Th2 type response to L. major due, in part, to their inability to sustain IL-12 responsiveness. The locus controlling this genetic effect maps to a region of chromosome 11 101, 102. Finally, although again not assessed for intestinal nematode parasites as yet, it has been suggested that the binding affinity of an antigenic determinant is crucial in the development of either Th1 or Th2, with peptides binding with low affinity to MHC Class II inducing a Th2 type response [103]. Thus, there are several factors which are important in determining the developmental pathway a naive T cell takes towards either Th1 or Th2. As the type of helper T cell response that develops has such a profound influence on host susceptibility or resistance to a pathogen, the factors involved in inducing a polarised response will no doubt become an even more intensely studied area.

Section snippets

General conclusions

Whilst it is difficult to make many generalisations, two common features are apparent.1. Resistance to intestinal nematode infections correlates with the ability to mount a CD4+ Th2 type response.2. Resistance to intestinal nematode infections is impaired by CD4+ Th1 type responses.The ability to expel an intestinal nematode infection clearly depends on CD4+ T cells that can make Th2 type cytokines. Although these cytokines typically include IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13 it is likely

Acknowledgements

We would like to thank our colleagues Dr Joe Urban, Dr Bill Gause, Dr Allison Bancroft and Dr Richard Grencis for their help over the years and for allowing us to discuss their unpublished data. We would also like to thank Dr Waliul Khan for permission to quote unpublished work and we are grateful to Richard Grencis for his helpful discussions and comments on the manuscript. The work from our laboratories has been supported by the Wellcome Trust (Grant No.44494\Z\95\Z) and NIH grants RO1

References (104)

  • JM Behnke et al.

    J Parasitol

    (1992)
  • ES Cooper et al.

    Parasitol Today

    (1988)
  • HRP Miller

    Vet Immunol Immunopathol

    (1984)
  • JF Jr Urban et al.

    Exp Parasitol

    (1991)
  • S Romagnani

    Immunol

    (1991)
  • Y Kamogawa et al.

    Cell

    (1993)
  • A O’Garra et al.

    Immunol

    (1994)
  • WE Paul et al.

    Cell

    (1994)
  • SJ Szabo et al.

    Immunity

    (1995)
  • RA Lawrence et al.

    Exp Parasitol

    (1996)
  • DE Williams et al.

    Cell

    (1990)
  • NG Copeland et al.

    Cell

    (1990)
  • KM Zsebo et al.

    Cell

    (1990)
  • E Huang et al.

    Cell

    (1990)
  • N Ishikawa et al.

    Gastroenterology

    (1997)
  • JF Koninkx et al.

    Exp Parasitol

    (1988)
  • VK Kuchroo et al.

    Cell

    (1995)
  • MS Chan et al.

    Parasitology

    (1994)
  • C Nokes et al.

    Parasitology

    (1992)
  • RM Maizels et al.

    Immunol

    (1993)
  • BM Ogilvie et al.

    J Parasitol

    (1968)
  • D Wakelin et al.

    Parasitology

    (1976)
  • KJ Else et al.

    Parasitology

    (1988)
  • FJ Enriquez et al.

    J Parasitol

    (1988)
  • JM Behnke et al.

    Parasite Immunol

    (1985)
  • RK Grencis et al.

    Immunology

    (1985)
  • IM Katona et al.

    J Immunol

    (1988)
  • K Koyama et al.

    Parasite Immunol

    (1995)
  • TR Mosmann et al.

    Immunol

    (1989)
  • O Abehsira-Amar et al.

    J Immunol

    (1992)
  • T Nakamura et al.

    J Immunol

    (1997)
  • CS Hsieh et al.

    Proc Natl Acad Sci USA

    (1992)
  • CS Hsieh et al.

    Science

    (1993)
  • RA Seder et al.

    Proc Natl Acad Sci USA

    (1993)
  • RA Seder et al.

    J Exp Med

    (1992)
  • CM Bacon et al.

    Proc Natl Acad Sci USA

    (1995)
  • NG Jacobson et al.

    J Exp Med

    (1995)
  • J Hou et al.

    Science

    (1994)
  • C Schindler et al.

    EMBO J

    (1994)
  • MK Kaplan et al.

    Nature

    (1996)
  • K Takeda et al.

    Nature

    (1996)
  • FW Fitch et al.

    Immunol

    (1993)
  • DF Fiorentino et al.

    J Exp Med

    (1989)
  • KJ Else et al.

    Immunology

    (1991)
  • KJ Else et al.

    Immunology

    (1992)
  • RK Grencis et al.

    Immunology

    (1991)
  • FN Wahid et al.

    Parasitology

    (1994)
  • FD Finkelman et al.

    Cytokine

    (1997)
  • RM Locksley et al.

    Immunol

    (1995)
  • JF Jr Urban et al.

    Proc Natl Acad Sci USA

    (1991)
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