Shaping the immune response to parasites: role of dendritic cells

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Abstract

Parasites represent a diverse group of pathogens that often trigger highly polarized immune responses that become tightly regulated during chronic infection. Recent studies have implicated the parasite–dendritic-cell interaction as a key determinant of the host response to these eukaryotic invaders. Dendritic cells appear to be pivotal in the initiation of cellular immunity against parasites as well as in directing Th1/Th2 effector choice. Moreover, there is increasing evidence that parasites regulate dendritic-cell function for the purposes of evading host immunity. This regulation also benefits parasites by protecting their host niche from the potentially lethal consequences of an uncontrolled inflammatory response.

Introduction

Parasites are eukaryotic pathogens that have evolved an intricate series of adaptations enabling them to survive for long periods of time in vivo, in most cases without inducing host mortality. A key set of adaptations concerns their encounter with the immune system; they must escape or suppress immune responses while at the same time avoiding overwhelming their hosts. As a consequence, host and parasite will have co-evolved a relationship characterized by tightly regulated immune responses. An unusual aspect of this host–pathogen interaction is the induction by parasites of CD4+ T cell responses that are highly polarized in terms of their Th1/Th2 lymphokine profiles. The phenomenon is particularly striking in the case of helminths, which, in contrast to nearly all other pathogens, routinely trigger strong Th2 responses, which are associated with high IgE levels, eosinophilia and mastocytosis. At the opposite pole, many intracellular protozoa (in common with their bacterial counterparts) induce CD4+ T-cell responses with Th1-dominated lymphokine secretion patterns [1].

The study of host–parasite models has provided a wealth of valuable information concerning T-lymphocyte function and regulation. In recent years, many investigators in the field have begun to focus their research on the role of antigen-presenting cells in initiating and modulating T-cell responses to the same pathogens. Much of this work has centered on dendritic cells (DCs) because of their unique capacity to sample sites of pathogen entry, respond to microbial signals and potently activate T cells. After internalizing and processing exogenous antigens in the periphery, DCs rapidly lose that function, undergo marked changes in morphology and motility and upregulate MHC class II, co-stimulatory and adhesion molecules. Although DC ‘maturation’ was originally viewed as an all-or-nothing event that follows pathogen encounter or exposure to inflammatory stimuli, and that readies DCs for interaction with naı̈ve T cells, this view has been modified to accommodate the wide range of changes in DC surface phenotype and cytokine profile resulting from pathogen recognition 2., 3..

Although all DCs originate from precursors in the bone marrow, fully differentiated DCs occur in distinct phenotypic subsets. Two major lineages, myeloid and plasmacytoid, are detected in mouse and man. In the mouse, myeloid DCs are further subdivided into CD8α+, CD4+, and CD8αCD4 (‘double negative’) subsets. Although specific immunologic functions as well as unique repertoires of pattern recognition receptors (PRRs) have been attributed to these subsets, the distinctions are seldom absolute and each appears to be capable of responding to a variety of microbial stimuli [4].

As summarized below, there is a growing literature indicating that the DC–parasite interaction is pivotal in both the triggering and the regulation of immunity to this important class of pathogens. At the same time, there is emerging evidence that DC function is itself modulated during parasitic infection for the mutual benefit of both host and parasite. This review summarizes recent developments in our understanding of how DCs both initiate and regulate immune responses to parasites as well as experimental approaches for intervention in parasitic disease based on the targeting of DC function.

Section snippets

Role of dendritic cells in initiation of parasite immune responses

Parasites and their products are clearly able to activate DCs and this interaction is believed to play a crucial role in initial T-cell priming. As plasmacytoid DCs have only recently been identified in mice, there are at present no data on whether parasites trigger this DC lineage. In the case of the myeloid lineage, a variety of protozoa have been shown to stimulate DC function [3]. In mice exposed to Toxoplasma gondii, the ability to produce IL-12 is limited to the CD8α+ DC subset and

Role of dendritic cells in effector choice

Since the early finding that they can respond to microbial stimuli by producing IL-12, it has been apparent that DCs can play a defining role in Th1 response induction. However, the view that IL-12 production by DCs is essential for Th1 response induction has been called into question recently by findings that T. gondii-infected IL-12−/− mice develop Th1 responses that are protective in the absence of IL-10 [22] and that IL-12−/− DCs pulsed with a strongly Th1-polarizing bacterial antigen,

Regulation of dendritic cell function during parasitic infection

It is important for both host and parasite that immune responses are carefully regulated in time and magnitude. In the case of DCs, such regulation can occur during the initial pathogen–host interaction as well as later during the establishment of chronic infection, and is now known to involve a variety of different mechanisms (Figure 3). Although, as discussed above, some parasites appear to avoid activating DC in the first place, there is growing evidence for more selective forms of

Dendritic-cell-based intervention strategies

Following the successes with DC-based vaccination against tumors, it is not surprising that similar approaches have been tried for parasitic infections. Although early experimental studies, notably in leishmaniasis 48., 49. and toxoplasmosis [50], were promising, the lack of obvious application in the context of infections occurring in mainly resource-poor countries has been an issue. Recent studies have concentrated more on DC-based therapy, although again this should be viewed more as a

Conclusions

It should be clear from this overview that encounter with parasites can strongly modify DC function and lead to altered T cell function in vitro and in vivo. Nonetheless, our understanding of this pathway is still at a relatively primitive stage. Although DC recognition of parasites is assumed to be mediated through TLRs, there are only a few examples of parasite molecules that trigger TLR signaling and even fewer examples of in vivo resistance against parasites dependent on the same

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

We thank Dragana Jankovic, Amy Straw, Julio Aliberti and Laura Cervi for their helpful comments on the manuscript.

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