Invited review
Neutrophils, dendritic cells and Toxoplasma

https://doi.org/10.1016/j.ijpara.2003.11.001Get rights and content

Abstract

Toxoplasma gondi rapidly elicits strong Type 1 cytokine-based immunity. The necessity for this response is well illustrated by the example of IFN-γ and IL-12 gene knockout mice that rapidly succumb to the effects of acute infection. The parasite itself is skilled at sparking complex interactions in the innate immune system that lead to protective immunity. Neutrophils are one of the first cell types to arrive at the site of infection, and the cells release several proinflammatory cytokines and chemokines in response to Toxoplasma. Dendritic cells are an important source of IL-12 during infection with T. gondii and other microbial pathogens, and they are also specialized for high-level antigen presentation to T lymphocytes. Tachyzoites express at least two types of molecules that trigger innate immune cell cytokine production. One of these involves Toll-like receptor/MyD88 pathways common to many microbial pathogens. The second pathway is less conventional and involves molecular mimicry between a parasite cyclophilin and host CC chemokine receptor 5-binding ligands. Neutrophils, dendritic cells and Toxoplasma work together to elicit the immune response required for host survival. Cytokine and chemokine cross-talk between parasite-triggered neutrophils and dendritic cells results in recruitment, maturation and activation of the latter. Neutrophil-empowered dendritic cells possess properties expected of highly potent antigen presenting cells that drive T helper 1 generation.

Introduction

Infection with the intracellular protozoan Toxoplasma gondii induces potent and long-lasting protective immunity (Alexander and Hunter, 1998, Denkers and Gazzinelli, 1998, Yap and Sher, 1999). Nevertheless, while highly effective, the immune response is not sufficient to eliminate the parasite. Instead, a balance is achieved through which the host and parasite maintain an equilibrium that can remain stable for the lifetime of the host. The pivotal role of immunity in the long-term stability of the host–pathogen interaction is most dramatically illustrated in the case of acquired immunodeficiency syndrome (AIDS) progression, where toxoplasmosis can emerge as a life-threatening infection associated with immune dysfunction (Luft and Remington, 1992). Toxoplasma gondii displays both inductive (reviewed here) and suppressive effects on the immune system (reviewed in Denkers et al., 2003b, Shapira et al., 2004). These dual properties likely account for the remarkable success of the parasite in human and animal populations worldwide.

The ability to survive T. gondii infection is critically dependent upon the parasite's ability to induce strong T cell-mediated immunity. Both CD4+ Th1 cells and CD8+ cytolytic T lymphocytes are vital in providing protective immunity and long-term survival during chronic infection, as determined by in vivo cell depletion studies and adoptive transfer of CD4+ and CD8+ T cell lines and clones (Gazzinelli et al., 1991, Gazzinelli et al., 1992, Parker et al., 1991, Kasper et al., 1992, Buzoni-Gatel et al., 1997, Suzuki and Remington, 1988). The protective property of these cell types is due to their ability to produce interferon (IFN)-γ, a proinflammatory cytokine that has become well known as the major mediator of resistance to Toxoplasma (Suzuki et al., 1988). Gene knockout mice that do not express IFN-γ cannot survive the acute phase of infection (Scharton-Kersten et al., 1996). Antibody-mediated depletion of this cytokine during chronic infection demonstrates that continued IFN-γ production is necessary for long-term survival (Gazzinelli et al., 1992). The cytokine exerts its anti-microbial activity through induction of specific effector molecules. The most important of these are reactive nitrogen intermediates that interfere with key metabolic enzymes (Khan et al., 1997, Scharton-Kersten et al., 1997, Roberts et al., 2000), indolamine 2,3-deoxygenase that induces tryptophan degradation (MacKenzie et al., 1999, Fujigaki et al., 2002, Silva et al., 2002), and a family of GTP-binding proteins whose function is currently obscure (Taylor et al., 2000, Collazo et al., 2001). While nitric oxide-dependent protection may be more important during chronic infection, the IFN-γ-inducible GTP-binding proteins IGTP and LRG-47 are required to survive acute T. gondii infection.

The strong cell-mediated immune response associated with Toxoplasma infection can be traced back to events that occur during initial encounter between the parasite and the host innate immune system. At this dynamic interface, cellular interactions are sparked that lead to T cell activation and IL-12-dependent Th1 differentiation. Polymorphonuclear leukocytes (PMN) and dendritic cells (DC) have recently emerged as key players in the inductive phase of immunity. Both cell types respond directly to T. gondii by secretion of cytokines and chemokines. New evidence, described below, also reveals that Toxoplasma stimulated cross-talk between neutrophils and DC results in enhanced activation and cytokine secretion by the latter (Bennouna et al., 2003).

Section snippets

Role of neutrophils during T. gondii infection

A hallmark characteristic of neutrophils is their ability to respond to an invading pathogen by rapidly migrating to the site of infection. Here, their classical function is widely regarded to be phagocytosis of pathogens, as well as release of microbicidal molecules such as reactive oxygen intermediates and degradative enzymes. We, and others, found that PMN depletion results in susceptibility to early T. gondii infection, but that removal of neutrophils has no effect on later stages of

Dendritic cell function during Toxoplasma infection

DC play a central role in presentation of antigen to T lymphocytes and controlling Th1 vs. Th2 differentiation during microbial infection. Their pattern of chemokine receptor expression changes upon activation suggesting a model in which tissue DC acquire microbial antigens, upregulate costimulatory molecule expression and cytokine production, then traffic to secondary lymphoid organs to activate naı̈ve T cells and induce T cell differentiation (Banchereau et al., 2000). More recent studies

Parasite factors that trigger innate immunity

Toxoplasma is highly adept at triggering cells of the innate immune system. From the standpoint of the parasite, it is advantageous to alert the host defence system to its presence. This is because T. gondii is a lethal infection in immunodeficient hosts, an outcome clearly unfavourable to parasite transmission. While well established that tachyzoites initiate activation and IL-12 release amongst cells of the innate immune system, only recently has a picture of the parasite molecules involved

Toxoplasma-triggered cross-talk between polymorphonuclear leukocytes and dendritic cells

Neutrophils are exquisitely tuned to the effects of infection, and accumulate rapidly in large numbers at sites of tissue damage or infection. The response is driven by chemotactic peptides released during inflammation that recruit PMN through binding to receptors such as CXCR2 (Del Rio et al., 2001, Tateda et al., 2001b). At the same time, tissue DC responds to many of the same chemokines and inflammatory mediators, resulting in exposure to microbial antigen and ultimately presentation to T

Conclusions and future challenges

Compelling evidence exists for cross-talk between DC and neutrophils, as well as between DC and other cell types. While some of the mediators involved have been identified (e.g. TNF-α and CCR5 ligands), many more soluble and cell surface molecules are likely to be important and remain to be identified. Recent progress has been made in identifying parasite molecules that activate both PMN and DC, but here again it is likely that more await elucidation. The most important challenges now are to

Acknowledgements

We thank past and present members of our laboratory for insightful discussions. Our work is supported by NIAID grant AI47888.

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