Introduction
There are over 10,000 species of parasitic protozoa, a subset of which can cause considerable disease in humans. Here we examine in detail the complex immune response generated during infection with a subset of these parasites: Trypanosoma cruzi, Leishmania sp, Toxoplasma gondii, and Plasmodium sp. For these organisms, their capacity to replicate inside host cells means that the ability of CD8+ T cells to recognize infected cells and respond with either cytolysis or the production of cytokines is critical for protection. While these particular species perhaps represent the most studied parasites in terms of understanding how T cells function during infection, it is clear that the lessons learned from this body of work are also relevant to the other protozoa known to induce a CD8+ T cell response. Nevertheless, despite major advances in defining the critical role of CD8+ T cells for long-term resistance to many parasites, there remains a paucity of vaccines for use in humans.
This review will highlight some of the key studies that established that CD8+ T cells play a major role in protective immunity to protozoa, the factors that promote the generation as well as maintenance of the CD8+ T cell response during these infections, and draw attention to some of the gaps in our knowledge. Moreover, the development of new tools, including MHC Class I tetramer reagents, TCR transgenic mice, and genetically modified parasites, has provided a better appreciation of how parasite specific CD8+ T cell responses are initiated and new insights into their phenotypic plasticity (Frickel et al., 2008; Garg et al., 1997; Hafalla et al., 2007; Kumar and Tarleton, 2001; Kwok et al., 2003; Martin et al., 2006; Miyakoda et al., 2008; Padilla et al., 2007; Pepper et al., 2004; Rodrigues et al., 1991). A greater understanding of the generation of the cellular immune response to these parasites will create new opportunities to develop effective vaccines for these organisms.
Public Health Impact of Parasitic Protozoa
Parasitic protozoa continue to pose major threats to human health and animals of veterinary importance. In addition, with the growing numbers of immunocompromised individuals, either as a consequence of acquired immunodeficiencies or because of specific treatments designed to suppress the immune system, there is a long list of normally asymptomatic or quiescent protozoal infections that can cause significant clinical disease (Ferreira and Borges, 2002). For example, while most humans are capable of mounting appropriate T cell responses required to control T. gondii, the decline in CD4+ T cell numbers and loss of CD8+ T cell function seen during AIDS can result in reactivation of latent T. gondii and the development of life threatening toxoplasmic encephalitis (Luft et al., 1984). T. cruzi and Leishmania sp., both organisms are normally associated with the inability to clear chronic infection, can also cause severe acute disease, or recrudesce as a consequence of HIV infection (Ferreira and Borges, 2002). The heaviest burden of morbidity and mortality following infection with Plasmodium sp. is found in children but there is also considerable disease associated with infection in adults. Further, despite having detectable CD8+ T cell responses to malaria antigens (Doolan et al., 1997; Plebanski et al., 1997; Sedegah et al., 1992), people in endemic areas suffer re-infection with Plasmodium many times over their lifetime (Good, 2005).
While alterations in immune status can profoundly alter the outcome of infection, changes in the parasite population structure can also have a significant impact on the ability of these organisms to cause disease. This is illustrated by recent reports that have noted atypical strains of T. gondii associated with ocular disease or acute lethality in immunocompetent individuals (Demar et al., 2007; Grigg et al., 2001; Khan et al., 2006). Similarly, outbreaks of acute Chagas disease in normal human populations, believed to have been transmitted orally, have recently been identified in Brazil (Nobrega et al., 2009; Steindel et al., 2008; Valente et al., 2009). Another example is the P. knowlesi strain of malaria, which infects macaques in Southeast Asia, but which has emerged as a threat to humans (Cox-Singh et al., 2008; Cox-Singh and Singh, 2008). The development of drug resistance is also a major problem, and this has been well-described in the case of malaria (Anderson, 2009; Khatoon et al., 2009; Pearce et al., 2009; Schonfeld et al., 2007; Schunk et al., 2006). Moreover, drug-resistant strains of T. cruzi, T. gondii and Leishmania have also emerged (Aspinall et al., 2002; Robello et al., 1997; Ubeda et al., 2008; Wilkinson et al., 2008) and this has accentuated the need for a better understanding of how the immune system can be used to limit infection.
Characterization of parasite specific CD8+ T cell responses in humans
While patients with defects in T cell mediated immunity illustrate the role of T cells in resistance to multiple intracellular parasites, numerous studies have characterized the T cell responses to these infections in humans. This work has focused on the ability of different T cell populations to make IFN-γ or lyse infected cells, two main effector functions of CD8+ T cells. For example, T. gondii-specific CD4+ as well as CD8+ T cells have been cloned from infected humans (Khan et al., 1990; Montoya et al., 1996; Purner et al., 1996), and another study noted a correlation of HLA haplotype with susceptibility to toxoplasmic encephalitis (Suzuki et al., 1996). Parasite-specific CD8+ T cells have also been isolated from the peripheral blood of T. cruzi-infected patients (Brodskyn et al., 1996; Wizel et al., 1998), and two other studies reported low frequencies of positive IFN-γ responses to predicted HLA-A2 CD8+ T cell epitopes (Fonseca et al., 2005; Laucella et al., 2004). CD8+ T cell responses to malaria circumsporozoite (CS) protein have also been identified following human infection (Braga et al., 2002; Doolan et al., 1993; Plebanski et al., 1997; Suphavilai et al., 2004), and this protein is a component of several candidate vaccines against malaria (Nardin et al., 2004; Oliveira et al., 2005; Wang et al., 2004). Further, even in the case of Leishmania where resistance is mainly mediated by CD4+ T cells, parasite-specific CD8+ T cells have been identified following human infection (Antonelli et al., 2004; Barral-Netto et al., 1995; Da-Cruz et al., 1994).
Defining the role of CD8+ T cells in animal models of parasitic infection
While the approaches discussed above highlight the presence of CD8+ T cell responses to parasites in humans, it is the development of experimental models that allowed the use of antibody depletion, adoptive transfers or knockout mice, that has clarified the role of this T cell subset in resistance to multiple infections. Some of the first evidence that an endogenous CD8+ T cell population was critical for resistance to a parasite was demonstrated when depletion of CD8+ T cells led to increased susceptibility to primary challenge with T. cruzi, associated with greatly increased parasite burdens (Tarleton, 1990). Subsequent studies showed that depletion of CD8+ T cells during the chronic stage resulted in the exacerbation of inflammation in the heart, the site of chronic T. cruzi infection, as well as higher parasite burden (Tarleton et al., 1994). Furthermore, β2-m–deficient mice, which lack the ability to express stable MHC class I molecules on the cell surface and therefore have minimal development of Class I-restricted CD8+ T cells, rapidly succumb to T. cruzi, thereby confirming the importance of CD8+ T cells in protection against this organism (Tarleton et al., 1992). This conclusion was complemented by studies in which the adoptive transfer of T. cruzi-specific CD8+ T cells protected mice against parasite challenge (Wizel et al., 1997).
Early studies to define the role of different lymphocyte populations in resistance to T. gondii were dependent on the use of a temperature-sensitive strain that provides protection from subsequent challenges (Suzuki et al., 1988). The transfer of T cells from infected or immunized mice to naïve mice provided protection against a lethal challenge of T. gondii, but this was abolished by depletion of CD8+ T cells prior to transfer (Parker et al., 1991; Suzuki and Remington, 1988). Similarly, transfer of CD8+ T cells from chronically infected mice to naïve WT or nude mice was also able to provide protection from T. gondii challenge (Parker et al., 1991). However, in the case of β2-m–deficient mice, a potent NK cell response could compensate for the lack of CD8+ T cells in response to T. gondii, though mice remained more susceptible than WT mice (Denkers et al., 1993b). Consistent with a protective role for CD8+ T cells, multiple genetic studies revealed that H-2 haplotype profoundly influenced the outcome of this infection (Brown and McLeod, 1990; Suzuki et al., 1994). While the initial studies focused on the ability of CD8+ T cells to protect against acute challenges, with the onset of the AIDS pandemic it became of interest to define which T cell populations were involved in preventing reactivation of T. gondii in the CNS. The finding that depletion of CD8+, but not CD4+, T cells during chronic infection led to increased mortality established the importance of these lymphocytes in long term resistance to toxoplasmic encephalitis (Gazzinelli et al., 1992a).
For Plasmodium, the ability of this organism to invade and replicate inside erythrocytes, which lack MHC class I expression, ensures little interaction of these infected cells with CD8+ T cells; but hepatocytes also get infected and can present parasite-derived antigens (Bongfen et al., 2007). Studies on the role of CD8+ T cells in resistance to malaria are contradictory: early studies showed that CD8+ T cell depletion had no effect on peak parasite titers but was associated with transient recrudescence of parasites in the blood (Podoba and Stevenson, 1991). However, β2-m-deficient mice have normal resolution of blood-stage malaria infection (van der Heyde et al., 1993). Adoptive transfer of CD8+ T cells could provide protection in some models (Khusmith et al., 1994; Mogil et al., 1987; Rodrigues et al., 1991), but not in others (Vinetz et al., 1990). Irradiated sporozoites, which target hepatocytes, have long been known to induce protective immunity to malaria (Nussenzweig et al., 1967) and multiple studies have shown that while neither CD4+ T cells or antibody is required for this immunity, CD8+ T cells are required for a protective response to the liver stage of this parasite (Doolan and Hoffman, 2000; Erb et al., 1996; Mueller et al., 2007; Romero et al., 2007; Tsuji and Zavala, 2003; Weiss et al., 1988).
CD4+ T cell production of IFN-γ is essential for protection against acute L. major and understanding the biology of T helper populations has been the main focus of study in resistance against this parasite (Launois et al., 1998; Moll et al., 1988; Reiner and Locksley, 1995). Much of the evidence does not support a protective role for CD8+ T cells in the control of primary challenge with Leishmania, as demonstrated by experiments in mice lacking CD8+ T cells or MHC-Class I expression where control of infection was not impaired (Huber et al., 1998; Overath and Harbecke, 1993; Wang et al., 1993). In MHC-Class II-deficient mice lacking CD4+ T cells, CD8+ T cells were not found to protect (Erb et al., 1996). However, several reports defined an important role for CD8+ T cells during Leishmania, either in memory responses or during low-dose intradermal challenge (Belkaid et al., 2002; Muller et al., 1993; Muller et al., 1994; Rafati et al., 2002; Uzonna et al., 2004). Adaptive immune responses against the parasites discussed herein are complex, and the outcome of the experiment may depend on dose or route of infection, or the strain of mouse that is infected. However, adaptive immune responses, and CD8+ T cells in particular, are clearly important for resistance to the parasites described in this review.
Antigen Presentation During Parasite Infection
Naïve CD8+ T cells are activated following exposure to their cognate antigen in the context of MHC I on the surface of antigen-presenting cells (APC). It was previously believed that only cell-associated endogenous antigens were presented by MHC Class I molecules. More recently, it has been appreciated that during transplant rejection as well as during viral or parasite infection that professional APC can sample and display exogenously-derived proteins on MHC I in the process of cross-presentation (Rock and Shen, 2005). Several studies, using a model of transient dendritic cell (DC) depletion, indicated that this pathway was critically required for generation of antigen-specific CD8+ T cells in mice infected with Listeria monocytogenes and P. yoelii (Jung et al., 2002; Liu et al., 2006). For malaria, transgenic parasites expressing the model antigen ovalbumin were used to show that Transporter Associated with Antigen Processing (TAP)-dependent cross-presentation of antigen begins shortly following infection, after APC travel to the skin draining LN (Miyakoda et al., 2008). TAP was not required for CD8+ T cell priming during L. major, nor was TAP required for resistance to infection, indicating that cross-priming occurs in a TAP-independent manner during this infection (Bertholet et al., 2006). In contrast, TAP was required to induce proliferation of T cells with T. gondii-infected DC (Bertholet et al., 2006) and another component of this TAP-dependent pathway, the ER-associated aminopeptidase, has also been implicated in antigen presentation and resistance to T. gondii (Blanchard et al., 2008). There is evidence in favor of (John et al., 2009), as well as against (Dzierszinski et al., 2007; Goldszmid et al., 2009; Gubbels et al., 2005), cross-presentation of antigen to CD8+ T cells during toxoplasmosis. Distinguishing which pathways are involved in these events may not just be of academic interest as they may determine the type of pathogen antigens that are presented to CD8+ T cells and therefore influence the generation of vaccine-mediated immunity.
The protozoan parasites that are the focus of this review all have relatively large microbial genomes, and this has complicated the discovery of relevant CD8+ T cell epitopes that would allow antigen processing and presentation to be studied more easily. Nevertheless, extensive efforts by many different groups have lead to the sequencing and annotation of the genomes of each of these organisms (El-Sayed et al., 2005; Gardner et al., 2002; Ivens et al., 2005; Kissinger et al., 2003), and formed the basis for the discovery of the endogenous CD8+ T cell epitopes from T. cruzi, T. gondii, and Plasmodium shown in Table I. One common theme has emerged from these studies, as well as from earlier reports using parasites that expressed model antigens: there appears to be preferential processing and presentation of antigens that are either secreted, or those located on the cell surface of these intracellular microbes (Bertholet et al., 2005; Garg et al., 1997; Gubbels et al., 2005; Pepper et al., 2004; Wilson et al., 2010). Therefore, targeting immune responses against surface-derived proteins would most likely be an effective vaccine approach.
Table I. Recent work in murine infection models of parasitic disease has identified endogenous CD8+ T cell epitopes.
CD8+ T Cell Epitopes in T. gondii, T. cruzi and P. falciparum
Parasite | Epitope | Gene family | References |
---|---|---|---|
T. cruzi | VDYNFTIV | Trans-sialidase | (Wizel et al., 1997) |
YEIQYVDL | Paraflagellar rod | (Wrightsman et al., 2002) | |
ELTMYKQLL | LYT1 (host cell lysis) | (Fralish and Tarleton, 2003) | |
ANYKFTLV | Trans-sialidase | (Martin et al., 2006) | |
| |||
T. gondii | SPMNGGYYM | Dense granule protein | (Frickel et al., 2008) |
IPAAAGRFF | Rhoptry protein | (Frickel et al., 2008) | |
SVLAFRRL | Putative secreted protein | (Wilson et al., 2010) | |
| |||
Plasmodium | NDDSYIPSAEKI | Circumsporozoite | (Romero et al., 1989) |
SYVPSAEQI | Circumsporozoite | (Rodrigues et al., 1991) |
Antigen recognition during parasite infection is further complicated by the distinct developmental stages associated with initiation of infection, development of disease and latency. For instance, T. gondii has been shown to express different antigens, depending on the stage of infection, with some antigens being expressed only during the tachyzoite stage, while others are not expressed until the parasite has encysted in the brain and muscle tissue in its bradyzoite form (Kim and Boothroyd, 2005; Kwok et al., 2003; Lutjen et al., 2006). Though changes in antigen expression can also occur during T. cruzi infection (Araya et al., 1994), an immunodominant CD8+ T cell epitope located in a trans-sialidase gene has been described which accounts for up to 30% of the antigen-specific CD8+ T cell response in certain inbred mouse strains (Martin et al., 2006). Many studies of antigen presentation during malaria infection have focused on the circumsporozite (CS) protein, which contains an immunodominant epitope, though work is on-going in order to identify other endogenous CD8+ epitopes from malaria parasites (Bongfen et al., 2007; Kumar et al., 2006; Plebanski et al., 2005) as well as those from the Leishmania genome (Herrera-Najera et al., 2009).
Anti-Parasitic Effector Mechanisms Mediated by CD8+ T Cells
With the recognition that CD8+ T cells play a role in limiting the replication of many different parasites, the next goal became to define how these lymphocytes mediated protection. IFN-γ is made by CD4+ and CD8+ T cells as well as NK cells, and has been demonstrated to be crucial for a protective response to numerous intracellular parasites by studies using neutralizing antibody to IFN-γ or mice deficient in its production (Scharton-Kersten et al., 1996; Schofield et al., 1987; Suzuki et al., 1989; Suzuki et al., 1988; Torrico et al., 1991). Evidence that production of this cytokine and subsequent protection against these parasitic diseases is dependent on CD8+ T cells was demonstrated by showing that treatment of infected mice with anti-CD8 antibodies resulted in reduced production of IFN-γ and loss of IFN-γ-mediated protection (Gazzinelli et al., 1991; Schofield et al., 1987; Shirahata et al., 1994; Tarleton, 1990; Weiss et al., 1988). Further, CD8+ T cells are also known to produce the pro-inflammatory cytokines IL-17 and TNF-α, and while both of these cytokines are associated with resistance to T. gondii, relatively little is known about the contribution of CD8+ T cells as a source of these factors during parasitic infections (Johnson, 1992; Kelly et al., 2005; Stumhofer et al., 2006).
CD8+ T cells can also mediate perforin-dependent cytotoxicity against target cells that present the correct peptide in the context of MHC on their cell surface. Early reports with T. gondii showed that CD8+ T cells isolated from immunized or infected mice were capable of lysing infected cells or targets pulsed with parasite antigens (Denkers et al., 1993a; Hakim et al., 1991; Khan et al., 1991; Subauste et al., 1991). These studies frequently relied on the in vitro expansion of rare T cell populations and the use of chromium release assays to demonstrate lytic activity. More recently, based on the development of in vivo cytotoxicity assays (Barber et al., 2003), cytotoxic CD8+ T cells have been detected in vivo during murine toxoplasmosis (Jordan et al., 2009), T. cruzi (Martin et al., 2006) and the blood stage of P. berghei (Lundie et al., 2008). However, the contribution of CD8-mediated cytolysis to resistance in vivo was uncertain until perforin-deficient mice became available. Initial studies with these mice revealed that they were less susceptible to infection than CD8-deficient mice, and could generate a protective CD8+ T cell response, but showed increased susceptibility to chronic toxoplasmosis indicating that the ability to recognize and lyse infected cells was required for optimal resistance (Denkers et al., 1993b; Denkers et al., 1997). In contrast, the cytolytic effector function of CD8+ T cells during malaria does not protect the host, but rather through perforin-mediated lysis of endothelial cells in the brain contributes to the pathology associated with cerebral malaria (Nitcheu et al., 2003; Potter et al., 2006).
Induction of CD8+ T Cell Responses
Many factors influence the generation of CD8+ T cell responses, including cytokines such as IL-2 and IL-12, which contribute to T cell expansion, survival, and the acquisition of effector function. CD4+ T cell help is important in the generation of effector CD8+ T cells following immunization with replication-deficient T. gondii (Jordan et al., 2009), but not during the acute stage of infection with a replicating strain of T. gondii (Lutjen et al., 2006). Work from two other groups found that CD4+ T cells were required to maintain optimal CD8+ T cell responses to T. gondii during chronic infection (Casciotti et al., 2002; Gazzinelli et al., 1992b). Following infection with irradiated malaria sporozoites, CD4+ T cell help was critical in the development of the CD8+ tetramer population (Carvalho et al., 2002), and in other malaria immunization models CD4+ T cell help also enhanced the CTL response (Valmori et al., 1994; Widmann et al., 1992). In contrast, antigen-specific CD8+ T cells specific for subdominant epitopes can develop during T. cruzi in the absence of CD4+ T cell help, but responses to dominant CD8+ T cell epitopes were CD4+ T cell dependent (Padilla et al., 2007). The seemingly disparate requirements for CD4+ T cell help might be explained by the inflammatory environment where priming occurs. When inflammation is limited, CD4+ T cells can have a significant role in promoting CD8+ T cell expansion through activating DC or providing growth factors such as IL-2 (Rajasagi et al., 2009; Wilson and Livingstone, 2008).
IL-12 was demonstrated to augment vaccine-induced responses to L. major and was thought to act as an adjuvant in that system (Afonso et al., 1994). Since that time it has been recognized that IL-12 can profoundly influence the generation, phenotype, and effector function of CD8+ T cells generated in response to T. gondii (Wilson et al., 2008), T. cruzi (Katae et al., 2002) and Plasmodium infection (Doolan and Hoffman, 1999), as well as playing a role during bacterial infection (Badovinac and Harty, 2007). Increasingly, it has also been demonstrated that while IL-12 can act as an adjuvant during the primary response to infection, its presence negatively affects the generation of CD8+ T cell memory responses (Joshi et al., 2007; Pearce and Shen, 2007; Takemoto et al., 2006). The role that IL-12 and other cytokines play in effector versus memory differentiation during parasite infection is still being unraveled, and it is likely that factors including duration of antigen exposure, cytokine milieu and priming environment will influence these events. The ability of a vaccine to induce CD4+ T cell help as well as cytokines that promote T cell differentiation, effector function, and memory formation must therefore be taken into consideration during vaccine design.
Regulation of Immune Responses During Chronic Infection
Parasite infection can induce mixed cytokine responses that differ based on mouse strain and may be linked with susceptibility or resistance to disease (Liesenfeld et al., 1996; Reiner and Locksley, 1995; Roggero et al., 2002; Zhang and Tarleton, 1996). While control of the parasites discussed within this review is generally dependent on robust Th1-polarized immune responses, these must be carefully controlled to prevent pathology in the host. In many studies mentioned above, pathological effects are mediated by CD4+ T cells rather than CD8+ T cells, one prominent exception being in the case of cerebral malaria where CTL caused damage to the brain via perforin-dependent mechanisms (Nitcheu et al., 2003). Immunoregulatory cytokines such as IL-10 and IL-27 are an important mechanism to limit these pro-inflammatory adaptive immune responses during chronic infection. For instance, IL-10−/− mice have increased susceptibility to T. gondii, P. chabaudi chabaudi and T. cruzi driven in part by overproduction of IFN-γ and TNF-α (Gazzinelli et al., 1996; Hunter et al., 1997; Li et al., 1999; Wilson et al., 2005). During experimental leishmaniasis IL-10 can either promote protection or the development of non-healing lesions, depending on the strain of parasite (Anderson et al., 2005; Kane and Mosser, 2001). Another more recently described cytokine, IL-27, has also been show to downregulate the inflammatory responses induced during T. gondii. This cytokine is important in limiting host pathology induced by IFN-γ (Villarino et al., 2003) as well as IL-17 (Stumhofer et al., 2006). IL-27 signaling also limits pro-inflammatory cytokine responses during T. cruzi (Hamano et al., 2003) while its role in L. major is more complex (Artis et al., 2004; Yoshida et al., 2001). Overall, these studies point to an important balance of the immune system as it attempts to combat invading pathogens, especially in the context of chronic infection.
CD8+ T Cell Memory in the Setting of Chronic Infection
Memory CD8+ T cell responses that develop following parasite infection have been defined functionally in terms of their ability to protect animals from secondary challenge (Gazzinelli et al., 1991; Muller et al., 1993; Parker et al., 1991; Schofield et al., 1987; Tarleton, 1990; Weiss et al., 1988). However, because many parasites cause persistent infections for the life of the individual, it can be difficult to phenotypically distinguish between chronically activated effectors and bona fide memory cells (Frenkel, 1988; Zhang and Tarleton, 1999). Memory CD8+ T cells induced by acute viral infection differ from what has been seen so far during parasite infection, and are characterized by their expression patterns of CD62L+KLRG1−CD127high (Joshi et al., 2007). The phenotype of CD8+ T cells during chronic toxoplasmosis or Chagas disease is that of an effector-memory cell as defined by their phenotype (CD62L−, KLRG1+ and CD127low) (Bixby and Tarleton, 2008; Bustamante et al., 2008). Drug-induced clearance of T. cruzi caused antigen-specific CD8+ T cells to upregulate their expression of CD62L, CD127 and CCR7 (Bustamante et al., 2008). These data indicate that ongoing antigen exposure was required for these cells to maintain an effector phenotype.
The fact that antigen-specific CD8+ T cells associated with some parasite infections are phenotypically different from viral memory cells, yet are able to protect mice from challenge, suggests that current paradigms for memory responses either need to be modified or recognized as being specific to different pathogens. Some of the same cytokines that have been associated with CD8+ T cell memory in viral and bacterial systems are also important in the development of CD8+ T cell memory during parasite infection; the importance of IL-7 and IL-15 in the survival and homeostatic proliferation of CD8+ T cells has recently been reviewed (Surh et al., 2006). For example, a subset of T. cruzi-specific CD8+ T cells was shown to be responsive to the cytokines IL-7 and IL-15 (Bixby and Tarleton, 2008). Thus, although memory cells are not yet as clearly defined as in other model systems, the same cytokines that contribute to the homeostasis of CD8+ T cells in viral models are likely important in maintaining similar populations during chronic parasite infection.
Targeting CD8+ T Cells for Anti-Parasitic Vaccines: What Comes Next?
Despite the advances in understanding the role of CD8+ T cells in immunity to multiple intracellular parasites, there are few vaccines against protozoan parasites. A vaccine to prevent Toxoplasma-induced abortions in cattle is commercially available (Buxton and Innes, 1995), but nothing approved for human use is currently available. The difficulty in developing vaccines against protozoan parasites could in part be attributed to the complicated life cycle of these organisms. Nevertheless, increasing the potency of current candidates, or development of therapeutic vaccines, would be helpful to limit the morbidity and mortality associated with certain parasitic infections. For example, recent work has shown that activation of the NF-κB signaling pathway in DC leads better antigen presentation, an approach that could be used as a generalized adjuvant during vaccination (Andreakos et al., 2006). A better understanding of the transcription factors that regulate the effector and memory potential of CD8+ T cells during parasite infection may provide additional strategies to increase the potency of vaccines. Multiple transcription factors that regulate CD8+ T cell effector functions, such as cytokine production and cytotoxicity, have been described in a range of infection models (Cho et al., 2009; Intlekofer et al., 2008; Intlekofer et al., 2005; Lieberman et al., 2004; Mason et al., 2004). However, further research is still required to understand how to best apply this information to promote the generation and maintenance of immunity to parasite infection.
Acknowledgments
KAJ was partly supported by a Cancer Research Institute training grant “Predoctoral Emphasis Pathway in Tumor Immunology” and CAH received funding from NIH AI 071302 and the State of Pennsylvania.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
References
- Afonso LC, Scharton TM, Vieira LQ, Wysocka M, Trinchieri G, Scott P. The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science. 1994;263:235–237. doi: 10.1126/science.7904381. [DOI] [PubMed] [Google Scholar]
- Anderson CF, Mendez S, Sacks DL. Nonhealing infection despite Th1 polarization produced by a strain of Leishmania major in C57BL/6 mice. Journal of Immunology. 2005;174:2934–2941. doi: 10.4049/jimmunol.174.5.2934. [DOI] [PubMed] [Google Scholar]
- Anderson T. Mapping the spread of malaria drug resistance. PLoS Med. 2009;6:e1000054. doi: 10.1371/journal.pmed.1000054. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Andreakos E, Williams RO, Wales J, Foxwell BM, Feldmann M. Activation of NF-kappaB by the intracellular expression of NF-kappaB-inducing kinase acts as a powerful vaccine adjuvant. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:14459–14464. doi: 10.1073/pnas.0603493103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Antonelli LR, Dutra WO, Almeida RP, Bacellar O, Gollob KJ. Antigen specific correlations of cellular immune responses in human leishmaniasis suggests mechanisms for immunoregulation. Clinical and Experimental Immunology. 2004;136:341–348. doi: 10.1111/j.1365-2249.2004.02426.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Araya JE, Cano MI, Yoshida N, da Silveira JF. Cloning and characterization of a gene for the stage-specific 82-kDa surface antigen of metacyclic trypomastigotes of Trypanosoma cruzi. Molecular and Biochemical Parasitology. 1994;65:161–169. doi: 10.1016/0166-6851(94)90124-4. [DOI] [PubMed] [Google Scholar]
- Artis D, Johnson LM, Joyce K, Saris C, Villarino A, Hunter CA, Scott P. Cutting edge: early IL-4 production governs the requirement for IL-27-WSX-1 signaling in the development of protective Th1 cytokine responses following Leishmania major infection. Journal of Immunology. 2004;172:4672–4675. doi: 10.4049/jimmunol.172.8.4672. [DOI] [PubMed] [Google Scholar]
- Aspinall TV, Joynson DH, Guy E, Hyde JE, Sims PF. The molecular basis of sulfonamide resistance in Toxoplasma gondii and implications for the clinical management of toxoplasmosis. Journal of Infectious Diseases. 2002;185:1637–1643. doi: 10.1086/340577. [DOI] [PubMed] [Google Scholar]
- Badovinac VP, Harty JT. Manipulating the rate of memory CD8+ T cell generation after acute infection. Journal of Immunology. 2007;179:53–63. doi: 10.4049/jimmunol.179.1.53. [DOI] [PubMed] [Google Scholar]
- Barber DL, Wherry EJ, Ahmed R. Cutting edge: rapid in vivo killing by memory CD8 T cells. Journal of Immunology. 2003;171:27–31. doi: 10.4049/jimmunol.171.1.27. [DOI] [PubMed] [Google Scholar]
- Barral-Netto M, Barral A, Brodskyn C, Carvalho EM, Reed SG. Cytotoxicity in human mucosal and cutaneous leishmaniasis. Parasite Immunology. 1995;17:21–28. doi: 10.1111/j.1365-3024.1995.tb00962.x. [DOI] [PubMed] [Google Scholar]
- Belkaid Y, Von Stebut E, Mendez S, Lira R, Caler E, Bertholet S, Udey MC, Sacks D. CD8+ T cells are required for primary immunity in C57BL/6 mice following low-dose, intradermal challenge with Leishmania major. Journal of Immunology. 2002;168:3992–4000. doi: 10.4049/jimmunol.168.8.3992. [DOI] [PubMed] [Google Scholar]
- Bertholet S, Debrabant A, Afrin F, Caler E, Mendez S, Tabbara KS, Belkaid Y, Sacks DL. Antigen requirements for efficient priming of CD8+ T cells by Leishmania major-infected dendritic cells. Infection and Immunity. 2005;73:6620–6628. doi: 10.1128/IAI.73.10.6620-6628.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bertholet S, Goldszmid R, Morrot A, Debrabant A, Afrin F, Collazo-Custodio C, Houde M, Desjardins M, Sher A, Sacks D. Leishmania antigens are presented to CD8+ T cells by a transporter associated with antigen processing-independent pathway in vitro and in vivo. Journal of Immunology. 2006;177:3525–3533. doi: 10.4049/jimmunol.177.6.3525. [DOI] [PubMed] [Google Scholar]
- Bixby LM, Tarleton RL. Stable CD8+ T cell memory during persistent Trypanosoma cruzi infection. Journal of Immunology. 2008;181:2644–2650. doi: 10.4049/jimmunol.181.4.2644. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blanchard N, Gonzalez F, Schaeffer M, Joncker NT, Cheng T, Shastri AJ, Robey EA, Shastri N. Immunodominant, protective response to the parasite Toxoplasma gondii requires antigen processing in the endoplasmic reticulum. Nat Immunol. 2008;9:937–944. doi: 10.1038/ni.1629. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bongfen SE, Torgler R, Romero JF, Renia L, Corradin G. Plasmodium berghei-infected primary hepatocytes process and present the circumsporozoite protein to specific CD8+ T cells in vitro. Journal of Immunology. 2007;178:7054–7063. doi: 10.4049/jimmunol.178.11.7054. [DOI] [PubMed] [Google Scholar]
- Braga EM, Carvalho LH, Fontes CJ, Krettli AU. Low cellular response in vitro among subjects with long-term exposure to malaria transmission in Brazilian endemic areas. American Journal of Tropical Medicine and Hygiene. 2002;66:299–303. doi: 10.4269/ajtmh.2002.66.299. [DOI] [PubMed] [Google Scholar]
- Brodskyn CI, Barral A, Bulhoes MA, Souto T, Machado WC, Barral-Netto M. Cytotoxicity in patients with different clinical forms of Chagas' disease. Clinical and Experimental Immunology. 1996;105:450–455. doi: 10.1046/j.1365-2249.1996.d01-785.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brown CR, McLeod R. Class I MHC genes and CD8+ T cells determine cyst number in Toxoplasma gondii infection. Journal of Immunology. 1990;145:3438–3441. [PubMed] [Google Scholar]
- Bustamante JM, Bixby LM, Tarleton RL. Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease. Nature Medicine. 2008;14:542–550. doi: 10.1038/nm1744. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Buxton D, Innes EA. A commercial vaccine for ovine toxoplasmosis. Parasitology. 1995;110 Suppl:S11–S16. doi: 10.1017/s003118200000144x. [DOI] [PubMed] [Google Scholar]
- Carvalho LH, Sano G, Hafalla JC, Morrot A, Curotto de Lafaille MA, Zavala F. IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages. Nature Medicine. 2002;8:166–170. doi: 10.1038/nm0202-166. [DOI] [PubMed] [Google Scholar]
- Casciotti L, Ely KH, Williams ME, Khan IA. CD8(+)-T-cell immunity against Toxoplasma gondii can be induced but not maintained in mice lacking conventional CD4(+) T cells. Infection and Immunity. 2002;70:434–443. doi: 10.1128/IAI.70.2.434-443.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cho OH, Shin HM, Miele L, Golde TE, Fauq A, Minter LM, Osborne BA. Notch regulates cytolytic effector function in CD8+ T cells. Journal of Immunology. 2009;182:3380–3389. doi: 10.4049/jimmunol.0802598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cox-Singh J, Davis TM, Lee KS, Shamsul SS, Matusop A, Ratnam S, Rahman HA, Conway DJ, Singh B. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clinical Infectious Diseases. 2008;46:165–171. doi: 10.1086/524888. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cox-Singh J, Singh B. Knowlesi malaria: newly emergent and of public health importance? Trends Parasitol. 2008;24:406–410. doi: 10.1016/j.pt.2008.06.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Da-Cruz AM, Conceicao-Silva F, Bertho AL, Coutinho SG. Leishmania-reactive CD4+ and CD8+ T cells associated with cure of human cutaneous leishmaniasis. Infection and Immunity. 1994;62:2614–2618. doi: 10.1128/iai.62.6.2614-2618.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Demar M, Ajzenberg D, Maubon D, Djossou F, Panchoe D, Punwasi W, Valery N, Peneau C, Daigre JL, Aznar C, et al. Fatal outbreak of human toxoplasmosis along the Maroni River: epidemiological, clinical, and parasitological aspects. Clinical Infectious Diseases. 2007;45:e88–e95. doi: 10.1086/521246. [DOI] [PubMed] [Google Scholar]
- Denkers EY, Gazzinelli RT, Hieny S, Caspar P, Sher A. Bone marrow macrophages process exogenous Toxoplasma gondii polypeptides for recognition by parasite-specific cytolytic T lymphocytes. Journal of Immunology. 1993a;150:517–526. [PubMed] [Google Scholar]
- Denkers EY, Gazzinelli RT, Martin D, Sher A. Emergence of NK1.1+ cells as effectors of IFN-gamma dependent immunity to Toxoplasma gondii in MHC class I-deficient mice. J Exp Med. 1993b;178:1465–1472. doi: 10.1084/jem.178.5.1465. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Denkers EY, Yap G, Scharton-Kersten T, Charest H, Butcher BA, Caspar P, Heiny S, Sher A. Perforin-mediated cytolysis plays a limited role in host resistance to Toxoplasma gondii. Journal of Immunology. 1997;159:1903–1908. [PubMed] [Google Scholar]
- Doolan DL, Hoffman SL. IL-12 and NK cells are required for antigen-specific adaptive immunity against malaria initiated by CD8+ T cells in the Plasmodium yoelii model. Journal of Immunology. 1999;163:884–892. [PubMed] [Google Scholar]
- Doolan DL, Hoffman SL. The complexity of protective immunity against liver-stage malaria. Journal of Immunology. 2000;165:1453–1462. doi: 10.4049/jimmunol.165.3.1453. [DOI] [PubMed] [Google Scholar]
- Doolan DL, Hoffman SL, Southwood S, Wentworth PA, Sidney J, Chesnut RW, Keogh E, Appella E, Nutman TB, Lal AA, et al. Degenerate cytotoxic T cell epitopes from P. falciparum restricted by multiple HLA-A and HLA-B supertype alleles. Immunity. 1997;7:97–112. doi: 10.1016/s1074-7613(00)80513-0. [DOI] [PubMed] [Google Scholar]
- Doolan DL, Khamboonruang C, Beck HP, Houghten RA, Good MF. Cytotoxic T lymphocyte (CTL) low-responsiveness to the Plasmodium falciparum circumsporozoite protein in naturally-exposed endemic populations: analysis of human CTL response to most known variants. International Immunology. 1993;5:37–46. doi: 10.1093/intimm/5.1.37. [DOI] [PubMed] [Google Scholar]
- Dzierszinski F, Pepper M, Stumhofer JS, LaRosa DF, Wilson EH, Turka LA, Halonen SK, Hunter CA, Roos DS. Presentation of Toxoplasma gondii antigens via the endogenous major histocompatibility complex class I pathway in nonprofessional and professional antigen-presenting cells. Infection and Immunity. 2007;75:5200–5209. doi: 10.1128/IAI.00954-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
- El-Sayed NM, Myler PJ, Bartholomeu DC, Nilsson D, Aggarwal G, Tran AN, Ghedin E, Worthey EA, Delcher AL, Blandin G, et al. The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science. 2005;309:409–415. doi: 10.1126/science.1112631. [DOI] [PubMed] [Google Scholar]
- Erb K, Blank C, Ritter U, Bluethmann H, Moll H. Leishmania major infection in major histocompatibility complex class II-deficient mice: CD8+ T cells do not mediate a protective immune response. Immunobiology. 1996;195:243–260. doi: 10.1016/S0171-2985(96)80043-X. [DOI] [PubMed] [Google Scholar]
- Ferreira MS, Borges AS. Some aspects of protozoan infections in immunocompromised patients- a review. Memorias do Instituto Oswaldo Cruz. 2002;97:443–457. doi: 10.1590/s0074-02762002000400001. [DOI] [PubMed] [Google Scholar]
- Fonseca SG, Moins-Teisserenc H, Clave E, Ianni B, Nunes VL, Mady C, Iwai LK, Sette A, Sidney J, Marin ML, et al. Identification of multiple HLA-A*0201-restricted cruzipain and FL-160 CD8+ epitopes recognized by T cells from chronically Trypanosoma cruzi-infected patients. Microbes Infect. 2005;7:688–697. doi: 10.1016/j.micinf.2005.01.001. [DOI] [PubMed] [Google Scholar]
- Frenkel JK. Pathophysiology of toxoplasmosis. Parasitol Today. 1988;4:273–278. doi: 10.1016/0169-4758(88)90018-x. [DOI] [PubMed] [Google Scholar]
- Frickel EM, Sahoo N, Hopp J, Gubbels MJ, Craver MP, Knoll LJ, Ploegh HL, Grotenbreg GM. Parasite stage-specific recognition of endogenous Toxoplasma gondii-derived CD8+ T cell epitopes. Journal of Infectious Diseases. 2008;198:1625–1633. doi: 10.1086/593019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature. 2002;419:498–511. doi: 10.1038/nature01097. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Garg N, Nunes MP, Tarleton RL. Delivery by Trypanosoma cruzi of proteins into the MHC class I antigen processing and presentation pathway. Journal of Immunology. 1997;158:3293–3302. [PubMed] [Google Scholar]
- Gazzinelli R, Xu Y, Hieny S, Cheever A, Sher A. Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. Journal of Immunology. 1992a;149:175–180. [PubMed] [Google Scholar]
- Gazzinelli RT, Hakim FT, Hieny S, Shearer GM, Sher A. Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine. Journal of Immunology. 1991;146:286–292. [PubMed] [Google Scholar]
- Gazzinelli RT, Hartley JW, Fredrickson TN, Chattopadhyay SK, Sher A, Morse HC., 3rd Opportunistic infections and retrovirus-induced immunodeficiency: studies of acute and chronic infections with Toxoplasma gondii in mice infected with LP-BM5 murine leukemia viruses. Infection and Immunity. 1992b;60:4394–4401. doi: 10.1128/iai.60.10.4394-4401.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kuhn R, Muller W, Trinchieri G, Sher A. In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha. Journal of Immunology. 1996;157:798–805. [PubMed] [Google Scholar]
- Goldszmid RS, Coppens I, Lev A, Caspar P, Mellman I, Sher A. Host ER-parasitophorous vacuole interaction provides a route of entry for antigen cross-presentation in Toxoplasma gondii-infected dendritic cells. Journal of Experimental Medicine. 2009;206:399–410. doi: 10.1084/jem.20082108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Good MF. Vaccine-induced immunity to malaria parasites and the need for novel strategies. Trends Parasitol. 2005;21:29–34. doi: 10.1016/j.pt.2004.10.006. [DOI] [PubMed] [Google Scholar]
- Grigg ME, Ganatra J, Boothroyd JC, Margolis TP. Unusual abundance of atypical strains associated with human ocular toxoplasmosis. Journal of Infectious Diseases. 2001;184:633–639. doi: 10.1086/322800. [DOI] [PubMed] [Google Scholar]
- Gubbels MJ, Striepen B, Shastri N, Turkoz M, Robey EA. Class I major histocompatibility complex presentation of antigens that escape from the parasitophorous vacuole of Toxoplasma gondii. Infection and Immunity. 2005;73:703–711. doi: 10.1128/IAI.73.2.703-711.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hafalla JC, Rai U, Bernal-Rubio D, Rodriguez A, Zavala F. Efficient development of plasmodium liver stage-specific memory CD8+ T cells during the course of blood-stage malarial infection. Journal of Infectious Diseases. 2007;196:1827–1835. doi: 10.1086/522965. [DOI] [PubMed] [Google Scholar]
- Hakim FT, Gazzinelli RT, Denkers E, Hieny S, Shearer GM, Sher A. CD8+ T cells from mice vaccinated against Toxoplasma gondii are cytotoxic for parasite-infected or antigen-pulsed host cells. Journal of Immunology. 1991;147:2310–2316. [PubMed] [Google Scholar]
- Hamano S, Himeno K, Miyazaki Y, Ishii K, Yamanaka A, Takeda A, Zhang M, Hisaeda H, Mak TW, Yoshimura A, Yoshida H. WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation of proinflammatory cytokine production. Immunity. 2003;19:657–667. doi: 10.1016/s1074-7613(03)00298-x. [DOI] [PubMed] [Google Scholar]
- Herrera-Najera C, Pina-Aguilar R, Xacur-Garcia F, Ramirez-Sierra MJ, Dumonteil E. Mining the Leishmania genome for novel antigens and vaccine candidates. Proteomics. 2009;9:1293–1301. doi: 10.1002/pmic.200800533. [DOI] [PubMed] [Google Scholar]
- Huber M, Timms E, Mak TW, Rollinghoff M, Lohoff M. Effective and long-lasting immunity against the parasite Leishmania major in CD8-deficient mice. Infection and Immunity. 1998;66:3968–3970. doi: 10.1128/iai.66.8.3968-3970.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hunter CA, Ellis-Neyes LA, Slifer T, Kanaly S, Grunig G, Fort M, Rennick D, Araujo FG. IL-10 is required to prevent immune hyperactivity during infection with Trypanosoma cruzi. Journal of Immunology. 1997;158:3311–3316. [PubMed] [Google Scholar]
- Intlekofer AM, Banerjee A, Takemoto N, Gordon SM, Dejong CS, Shin H, Hunter CA, Wherry EJ, Lindsten T, Reiner SL. Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science. 2008;321:408–411. doi: 10.1126/science.1159806. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Intlekofer AM, Takemoto N, Wherry EJ, Longworth SA, Northrup JT, Palanivel VR, Mullen AC, Gasink CR, Kaech SM, Miller JD, et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol. 2005;6:1236–1244. doi: 10.1038/ni1268. [DOI] [PubMed] [Google Scholar]
- Ivens AC, Peacock CS, Worthey EA, Murphy L, Aggarwal G, Berriman M, Sisk E, Rajandream MA, Adlem E, Aert R, et al. The genome of the kinetoplastid parasite, Leishmania major. Science. 2005;309:436–442. doi: 10.1126/science.1112680. [DOI] [PMC free article] [PubMed] [Google Scholar]
- John B, Harris TH, Tait ED, Wilson EH, Gregg B, Ng LG, Mrass P, Roos DS, Dzierszinski F, Weninger W, Hunter CA. Dynamic Imaging of CD8(+) T cells and dendritic cells during infection with Toxoplasma gondii. PLoS Pathog. 2009;5:e1000505. doi: 10.1371/journal.ppat.1000505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Johnson LL. A protective role for endogenous tumor necrosis factor in Toxoplasma gondii infection. Infection and Immunity. 1992;60:1979–1983. doi: 10.1128/iai.60.5.1979-1983.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jordan KA, Wilson EH, Tait ED, Fox BA, Roos DS, Bzik DJ, Dzierszinski F, Hunter CA. Kinetics and phenotype of vaccine-induced CD8+ T-cell responses to Toxoplasma gondii. Infection and Immunity. 2009;77:3894–3901. doi: 10.1128/IAI.00024-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Joshi NS, Cui W, Chandele A, Lee HK, Urso DR, Hagman J, Gapin L, Kaech SM. Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity. 2007;27:281–295. doi: 10.1016/j.immuni.2007.07.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jung S, Unutmaz D, Wong P, Sano G, De los Santos K, Sparwasser T, Wu S, Vuthoori S, Ko K, Zavala F, et al. In vivo depletion of CD11c(+) dendritic cells abrogates priming of CD8(+) T cells by exogenous cell-associated antigens. Immunity. 2002;17:211–220. doi: 10.1016/s1074-7613(02)00365-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kane MM, Mosser DM. The role of IL-10 in promoting disease progression in leishmaniasis. Journal of Immunology. 2001;166:1141–1147. doi: 10.4049/jimmunol.166.2.1141. [DOI] [PubMed] [Google Scholar]
- Katae M, Miyahira Y, Takeda K, Matsuda H, Yagita H, Okumura K, Takeuchi T, Kamiyama T, Ohwada A, Fukuchi Y, Aoki T. Coadministration of an interleukin-12 gene and a Trypanosoma cruzi gene improves vaccine efficacy. Infection and Immunity. 2002;70:4833–4840. doi: 10.1128/IAI.70.9.4833-4840.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kelly MN, Kolls JK, Happel K, Schwartzman JD, Schwarzenberger P, Combe C, Moretto M, Khan IA. Interleukin-17/interleukin-17 receptor-mediated signaling is important for generation of an optimal polymorphonuclear response against Toxoplasma gondii infection. Infection and Immunity. 2005;73:617–621. doi: 10.1128/IAI.73.1.617-621.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Khan A, Jordan C, Muccioli C, Vallochi AL, Rizzo LV, Belfort R, Jr, Vitor RW, Silveira C, Sibley LD. Genetic divergence of Toxoplasma gondii strains associated with ocular toxoplasmosis, Brazil. Emerging Infectious Diseases. 2006;12:942–949. doi: 10.3201/eid1206.060025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Khan IA, Ely KH, Kasper LH. A purified parasite antigen (p30) mediates CD8+ T cell immunity against fatal Toxoplasma gondii infection in mice. Journal of Immunology. 1991;147:3501–3506. [PubMed] [Google Scholar]
- Khan IA, Smith KA, Kasper LH. Induction of antigen-specific human cytotoxic T cells by Toxoplasma gondii. Journal of Clinical Investigation. 1990;85:1879–1886. doi: 10.1172/JCI114649. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Khatoon L, Baliraine FN, Bonizzoni M, Malik SA, Yan G. Prevalence of antimalarial drug resistance mutations in Plasmodium vivax and P. falciparum from a malaria-endemic area of Pakistan. American Journal of Tropical Medicine and Hygiene. 2009;81:525–528. [PMC free article] [PubMed] [Google Scholar]
- Khusmith S, Sedegah M, Hoffman SL. Complete protection against Plasmodium yoelii by adoptive transfer of a CD8+ cytotoxic T-cell clone recognizing sporozoite surface protein 2. Infection and Immunity. 1994;62:2979–2983. doi: 10.1128/iai.62.7.2979-2983.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kim SK, Boothroyd JC. Stage-specific expression of surface antigens by Toxoplasma gondii as a mechanism to facilitate parasite persistence. Journal of Immunology. 2005;174:8038–8048. doi: 10.4049/jimmunol.174.12.8038. [DOI] [PubMed] [Google Scholar]
- Kissinger JC, Gajria B, Li L, Paulsen IT, Roos DS. ToxoDB: accessing the Toxoplasma gondii genome. Nucleic Acids Res. 2003;31:234–236. doi: 10.1093/nar/gkg072. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kumar KA, Sano G, Boscardin S, Nussenzweig RS, Nussenzweig MC, Zavala F, Nussenzweig V. The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites. Nature. 2006;444:937–940. doi: 10.1038/nature05361. [DOI] [PubMed] [Google Scholar]
- Kumar S, Tarleton RL. Antigen-specific Th1 but not Th2 cells provide protection from lethal Trypanosoma cruzi infection in mice. Journal of Immunology. 2001;166:4596–4603. doi: 10.4049/jimmunol.166.7.4596. [DOI] [PubMed] [Google Scholar]
- Kwok LY, Lutjen S, Soltek S, Soldati D, Busch D, Deckert M, Schluter D. The induction and kinetics of antigen-specific CD8 T cells are defined by the stage specificity and compartmentalization of the antigen in murine toxoplasmosis. Journal of Immunology. 2003;170:1949–1957. doi: 10.4049/jimmunol.170.4.1949. [DOI] [PubMed] [Google Scholar]
- Laucella SA, Postan M, Martin D, Hubby Fralish B, Albareda MC, Alvarez MG, Lococo B, Barbieri G, Viotti RJ, Tarleton RL. Frequency of interferon- gamma -producing T cells specific for Trypanosoma cruzi inversely correlates with disease severity in chronic human Chagas disease. Journal of Infectious Diseases. 2004;189:909–918. doi: 10.1086/381682. [DOI] [PubMed] [Google Scholar]
- Launois P, Conceicao-Silva F, Himmerlich H, Parra-Lopez C, Tacchini-Cottier F, Louis JA. Setting in motion the immune mechanisms underlying genetically determined resistance and susceptibility to infection with Leishmania major. Parasite Immunology. 1998;20:223–230. doi: 10.1046/j.1365-3024.1998.00153.x. [DOI] [PubMed] [Google Scholar]
- Li C, Corraliza I, Langhorne J. A defect in interleukin-10 leads to enhanced malarial disease in Plasmodium chabaudi chabaudi infection in mice. Infection and Immunity. 1999;67:4435–4442. doi: 10.1128/iai.67.9.4435-4442.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lieberman LA, Banica M, Reiner SL, Hunter CA. STAT1 plays a critical role in the regulation of antimicrobial effector mechanisms, but not in the development of Th1-type responses during toxoplasmosis. J Immunol. 2004;172:457–463. doi: 10.4049/jimmunol.172.1.457. [DOI] [PubMed] [Google Scholar]
- Liesenfeld O, Kosek J, Remington JS, Suzuki Y. Association of CD4+ T cell-dependent, interferon-gamma-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii. Journal of Experimental Medicine. 1996;184:597–607. doi: 10.1084/jem.184.2.597. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu CH, Fan YT, Dias A, Esper L, Corn RA, Bafica A, Machado FS, Aliberti J. Cutting edge: dendritic cells are essential for in vivo IL-12 production and development of resistance against Toxoplasma gondii infection in mice. Journal of Immunology. 2006;177:31–35. doi: 10.4049/jimmunol.177.1.31. [DOI] [PubMed] [Google Scholar]
- Luft BJ, Brooks RG, Conley FK, McCabe RE, Remington JS. Toxoplasmic encephalitis in patients with acquired immune deficiency syndrome. JAMA. 1984;252:913–917. [PubMed] [Google Scholar]
- Lundie RJ, de Koning-Ward TF, Davey GM, Nie CQ, Hansen DS, Lau LS, Mintern JD, Belz GT, Schofield L, Carbone FR, et al. Blood-stage Plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8alpha+ dendritic cells. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:14509–14514. doi: 10.1073/pnas.0806727105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lutjen S, Soltek S, Virna S, Deckert M, Schluter D. Organ- and disease-stage-specific regulation of Toxoplasma gondii-specific CD8-T-cell responses by CD4 T cells. Infection and Immunity. 2006;74:5790–5801. doi: 10.1128/IAI.00098-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Martin DL, Weatherly DB, Laucella SA, Cabinian MA, Crim MT, Sullivan S, Heiges M, Craven SH, Rosenberg CS, Collins MH, et al. CD8+ T- Cell responses to Trypanosoma cruzi are highly focused on strain-variant trans-sialidase epitopes. PLoS Pathog. 2006;2:e77. doi: 10.1371/journal.ppat.0020077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mason NJ, Liou HC, Hunter CA. T cell-intrinsic expression of c-Rel regulates Th1 cell responses essential for resistance to Toxoplasma gondii. Journal of Immunology. 2004;172:3704–3711. doi: 10.4049/jimmunol.172.6.3704. [DOI] [PubMed] [Google Scholar]
- Miyakoda M, Kimura D, Yuda M, Chinzei Y, Shibata Y, Honma K, Yui K. Malaria-specific and nonspecific activation of CD8+ T cells during blood stage of Plasmodium berghei infection. Journal of Immunology. 2008;181:1420–1428. doi: 10.4049/jimmunol.181.2.1420. [DOI] [PubMed] [Google Scholar]
- Mogil RJ, Patton CL, Green DR. Cellular subsets involved in cell-mediated immunity to murine Plasmodium yoelii 17X malaria. Journal of Immunology. 1987;138:1933–1939. [PubMed] [Google Scholar]
- Moll H, Scollay R, Mitchell GF. Resistance to cutaneous leishmaniasis in nude mice injected with L3T4+ T cells but not with Ly-2+ T cells. Immunology and Cell Biology. 1988;66(Pt 1):57–63. doi: 10.1038/icb.1988.7. [DOI] [PubMed] [Google Scholar]
- Montoya JG, Lowe KE, Clayberger C, Moody D, Do D, Remington JS, Talib S, Subauste CS. Human CD4+ and CD8+ T lymphocytes are both cytotoxic to Toxoplasma gondii-infected cells. Infection and Immunity. 1996;64:176–181. doi: 10.1128/iai.64.1.176-181.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mueller AK, Deckert M, Heiss K, Goetz K, Matuschewski K, Schluter D. Genetically attenuated Plasmodium berghei liver stages persist and elicit sterile protection primarily via CD8 T cells. American Journal of Pathology. 2007;171:107–115. doi: 10.2353/ajpath.2007.060792. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Muller I, Kropf P, Etges RJ, Louis JA. Gamma interferon response in secondary Leishmania major infection: role of CD8+ T cells. Infection and Immunity. 1993;61:3730–3738. doi: 10.1128/iai.61.9.3730-3738.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Muller I, Kropf P, Louis JA, Milon G. Expansion of gamma interferon-producing CD8+ T cells following secondary infection of mice immune to Leishmania major. Infection and Immunity. 1994;62:2575–2581. doi: 10.1128/iai.62.6.2575-2581.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nardin EH, Oliveira GA, Calvo-Calle JM, Wetzel K, Maier C, Birkett AJ, Sarpotdar P, Corado ML, Thornton GB, Schmidt A. Phase I testing of a malaria vaccine composed of hepatitis B virus core particles expressing Plasmodium falciparum circumsporozoite epitopes. Infection and Immunity. 2004;72:6519–6527. doi: 10.1128/IAI.72.11.6519-6527.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nitcheu J, Bonduelle O, Combadiere C, Tefit M, Seilhean D, Mazier D, Combadiere B. Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis. Journal of Immunology. 2003;170:2221–2228. doi: 10.4049/jimmunol.170.4.2221. [DOI] [PubMed] [Google Scholar]
- Nobrega AA, Garcia MH, Tatto E, Obara MT, Costa E, Sobel J, Araujo WN. Oral transmission of Chagas disease by consumption of acai palm fruit, Brazil. Emerging Infectious Diseases. 2009;15:653–655. doi: 10.3201/eid1504.081450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nussenzweig RS, Vanderberg J, Most H, Orton C. Protective immunity produced by the injection of x-irradiated sporozoites of plasmodium berghei. Nature. 1967;216:160–162. doi: 10.1038/216160a0. [DOI] [PubMed] [Google Scholar]
- Oliveira GA, Wetzel K, Calvo-Calle JM, Nussenzweig R, Schmidt A, Birkett A, Dubovsky F, Tierney E, Gleiter CH, Boehmer G, et al. Safety and enhanced immunogenicity of a hepatitis B core particle Plasmodium falciparum malaria vaccine formulated in adjuvant Montanide ISA 720 in a phase I trial. Infection and Immunity. 2005;73:3587–3597. doi: 10.1128/IAI.73.6.3587-3597.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Overath P, Harbecke D. Course of Leishmania infection in beta 2-microglobulin-deficient mice. Immunology Letters. 1993;37:13–17. doi: 10.1016/0165-2478(93)90126-m. [DOI] [PubMed] [Google Scholar]
- Padilla A, Xu D, Martin D, Tarleton R. Limited role for CD4+ T-cell help in the initial priming of Trypanosoma cruzi-specific CD8+ T cells. Infection and Immunity. 2007;75:231–235. doi: 10.1128/IAI.01245-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Parker SJ, Roberts CW, Alexander J. CD8+ T cells are the major lymphocyte subpopulation involved in the protective immune response to Toxoplasma gondii in mice. Clinical and Experimental Immunology. 1991;84:207–212. doi: 10.1111/j.1365-2249.1991.tb08150.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pearce EL, Shen H. Generation of CD8 T cell memory is regulated by IL-12. Journal of Immunology. 2007;179:2074–2081. doi: 10.4049/jimmunol.179.4.2074. [DOI] [PubMed] [Google Scholar]
- Pearce RJ, Pota H, Evehe MS, Ba el H, Mombo-Ngoma G, Malisa AL, Ord R, Inojosa W, Matondo A, Diallo DA, et al. Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria. PLoS Med. 2009;6:e1000055. doi: 10.1371/journal.pmed.1000055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pepper M, Dzierszinski F, Crawford A, Hunter CA, Roos D. Development of a system to study CD4+-T-cell responses to transgenic ovalbumin-expressing Toxoplasma gondii during toxoplasmosis. Infection and Immunity. 2004;72:7240–7246. doi: 10.1128/IAI.72.12.7240-7246.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Plebanski M, Aidoo M, Whittle HC, Hill AV. Precursor frequency analysis of cytotoxic T lymphocytes to pre-erythrocytic antigens of Plasmodium falciparum in West Africa. Journal of Immunology. 1997;158:2849–2855. [PubMed] [Google Scholar]
- Plebanski M, Hannan CM, Behboudi S, Flanagan KL, Apostolopoulos V, Sinden RE, Hill AV. Direct processing and presentation of antigen from malaria sporozoites by professional antigen-presenting cells in the induction of CD8 T-cell responses. Immunology and Cell Biology. 2005;83:307–312. doi: 10.1111/j.1440-1711.2005.01325.x. [DOI] [PubMed] [Google Scholar]
- Podoba JE, Stevenson MM. CD4+ and CD8+ T lymphocytes both contribute to acquired immunity to blood-stage Plasmodium chabaudi AS. Infection and Immunity. 1991;59:51–58. doi: 10.1128/iai.59.1.51-58.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Potter S, Chan-Ling T, Ball HJ, Mansour H, Mitchell A, Maluish L, Hunt NH. Perforin mediated apoptosis of cerebral microvascular endothelial cells during experimental cerebral malaria. International Journal for Parasitology. 2006;36:485–496. doi: 10.1016/j.ijpara.2005.12.005. [DOI] [PubMed] [Google Scholar]
- Purner MB, Berens RL, Nash PB, van Linden A, Ross E, Kruse C, Krug EC, Curiel TJ. CD4-mediated and CD8-mediated cytotoxic and proliferative immune responses to Toxoplasma gondii in seropositive humans. Infection and Immunity. 1996;64:4330–4338. doi: 10.1128/iai.64.10.4330-4338.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rafati S, Kariminia A, Seyde-Eslami S, Narimani M, Taheri T, Lebbatard M. Recombinant cysteine proteinases-based vaccines against Leishmania major in BALB/c mice: the partial protection relies on interferon gamma producing CD8(+) T lymphocyte activation. Vaccine. 2002;20:2439–2447. doi: 10.1016/s0264-410x(02)00189-5. [DOI] [PubMed] [Google Scholar]
- Rajasagi NK, Kassim SH, Kollias CM, Zhao X, Chervenak R, Jennings SR. CD4+ T cells are required for the priming of CD8+ T cells following infection with herpes simplex virus type 1. Journal of Virology. 2009;83:5256–5268. doi: 10.1128/JVI.01997-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reiner SL, Locksley RM. The regulation of immunity to Leishmania major. Annual Review of Immunology. 1995;13:151–177. doi: 10.1146/annurev.iy.13.040195.001055. [DOI] [PubMed] [Google Scholar]
- Robello C, Navarro P, Castanys S, Gamarro F. A pteridine reductase gene ptr1 contiguous to a P-glycoprotein confers resistance to antifolates in Trypanosoma cruzi. Molecular and Biochemical Parasitology. 1997;90:525–535. doi: 10.1016/s0166-6851(97)00207-7. [DOI] [PubMed] [Google Scholar]
- Rock KL, Shen L. Cross-presentation: underlying mechanisms and role in immune surveillance. Immunological Reviews. 2005;207:166–183. doi: 10.1111/j.0105-2896.2005.00301.x. [DOI] [PubMed] [Google Scholar]
- Rodrigues MM, Cordey AS, Arreaza G, Corradin G, Romero P, Maryanski JL, Nussenzweig RS, Zavala F. CD8+ cytolytic T cell clones derived against the Plasmodium yoelii circumsporozoite protein protect against malaria. International Immunology. 1991;3:579–585. doi: 10.1093/intimm/3.6.579. [DOI] [PubMed] [Google Scholar]
- Roggero E, Perez A, Tamae-Kakazu M, Piazzon I, Nepomnaschy I, Wietzerbin J, Serra E, Revelli S, Bottasso O. Differential susceptibility to acute Trypanosoma cruzi infection in BALB/c and C57BL/6 mice is not associated with a distinct parasite load but cytokine abnormalities. Clinical and Experimental Immunology. 2002;128:421–428. doi: 10.1046/j.1365-2249.2002.01874.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Romero JF, Ibrahim GH, Renggli J, Himmelrich H, Graber P, Corradin G. IL-12p40-independent induction of protective immunity upon multiple Plasmodium berghei irradiated sporozoite immunizations. Parasite Immunology. 2007;29:541–548. doi: 10.1111/j.1365-3024.2007.00972.x. [DOI] [PubMed] [Google Scholar]
- Scharton-Kersten TM, Wynn TA, Denkers EY, Bala S, Grunvald E, Hieny S, Gazzinelli RT, Sher A. In the absence of endogenous IFN-gamma, mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection. Journal of Immunology. 1996;157:4045–4054. [PubMed] [Google Scholar]
- Schofield L, Villaquiran J, Ferreira A, Schellekens H, Nussenzweig R, Nussenzweig V. Gamma interferon, CD8+ T cells and antibodies required for immunity to malaria sporozoites. Nature. 1987;330:664–666. doi: 10.1038/330664a0. [DOI] [PubMed] [Google Scholar]
- Schonfeld M, Barreto Miranda I, Schunk M, Maduhu I, Maboko L, Hoelscher M, Berens-Riha N, Kitua A, Loscher T. Molecular surveillance of drug-resistance associated mutations of Plasmodium falciparum in south-west Tanzania. Malar J. 2007;6:2. doi: 10.1186/1475-2875-6-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schunk M, Kumma WP, Miranda IB, Osman ME, Roewer S, Alano A, Loscher T, Bienzle U, Mockenhaupt FP. High prevalence of drug-resistance mutations in Plasmodium falciparum and Plasmodium vivax in southern Ethiopia. Malar J. 2006;5:54. doi: 10.1186/1475-2875-5-54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sedegah M, Sim BK, Mason C, Nutman T, Malik A, Roberts C, Johnson A, Ochola J, Koech D, Were B, et al. Naturally acquired CD8+ cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein. Journal of Immunology. 1992;149:966–971. [PubMed] [Google Scholar]
- Shirahata T, Yamashita T, Ohta C, Goto H, Nakane A. CD8+ T lymphocytes are the major cell population involved in the early gamma interferon response and resistance to acute primary Toxoplasma gondii infection in mice. Microbiology and Immunology. 1994;38:789–796. doi: 10.1111/j.1348-0421.1994.tb01858.x. [DOI] [PubMed] [Google Scholar]
- Steindel M, Kramer Pacheco L, Scholl D, Soares M, de Moraes MH, Eger I, Kosmann C, Sincero TC, Stoco PH, Murta SM, et al. Characterization of Trypanosoma cruzi isolated from humans, vectors, and animal reservoirs following an outbreak of acute human Chagas disease in Santa Catarina State, Brazil. Diagnostic Microbiology and Infectious Disease. 2008;60:25–32. doi: 10.1016/j.diagmicrobio.2007.07.016. [DOI] [PubMed] [Google Scholar]
- Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, Villarino AV, Huang Q, Yoshimura A, Sehy D, et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol. 2006;7:937–945. doi: 10.1038/ni1376. [DOI] [PubMed] [Google Scholar]
- Subauste CS, Koniaris AH, Remington JS. Murine CD8+ cytotoxic T lymphocytes lyse Toxoplasma gondii-infected cells. Journal of Immunology. 1991;147:3955–3959. [PubMed] [Google Scholar]
- Suphavilai C, Looareesuwan S, Good MF. Analysis of circumsporozoite protein-specific immune responses following recent infection with Plasmodium vivax. American Journal of Tropical Medicine and Hygiene. 2004;71:29–39. [PubMed] [Google Scholar]
- Surh CD, Boyman O, Purton JF, Sprent J. Homeostasis of memory T cells. Immunological Reviews. 2006;211:154–163. doi: 10.1111/j.0105-2896.2006.00401.x. [DOI] [PubMed] [Google Scholar]
- Suzuki Y, Conley FK, Remington JS. Importance of endogenous IFN-gamma for prevention of toxoplasmic encephalitis in mice. Journal of Immunology. 1989;143:2045–2050. [PubMed] [Google Scholar]
- Suzuki Y, Joh K, Kwon OC, Yang Q, Conley FK, Remington JS. MHC class I gene(s) in the D/L region but not the TNF-alpha gene determines development of toxoplasmic encephalitis in mice. Journal of Immunology. 1994;153:4649–4654. [PubMed] [Google Scholar]
- Suzuki Y, Orellana MA, Schreiber RD, Remington JS. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science. 1988;240:516–518. doi: 10.1126/science.3128869. [DOI] [PubMed] [Google Scholar]
- Suzuki Y, Remington JS. Dual regulation of resistance against Toxoplasma gondii infection by Lyt-2+ and Lyt-1+, L3T4+ T cells in mice. Journal of Immunology. 1988;140:3943–3946. [PubMed] [Google Scholar]
- Suzuki Y, Wong SY, Grumet FC, Fessel J, Montoya JG, Zolopa AR, Portmore A, Schumacher-Perdreau F, Schrappe M, Koppen S, et al. Evidence for genetic regulation of susceptibility to toxoplasmic encephalitis in AIDS patients. Journal of Infectious Diseases. 1996;173:265–268. doi: 10.1093/infdis/173.1.265. [DOI] [PubMed] [Google Scholar]
- Takemoto N, Intlekofer AM, Northrup JT, Wherry EJ, Reiner SL. Cutting Edge: IL-12 inversely regulates T-bet and eomesodermin expression during pathogen-induced CD8+ T cell differentiation. Journal of Immunology. 2006;177:7515–7519. doi: 10.4049/jimmunol.177.11.7515. [DOI] [PubMed] [Google Scholar]
- Tarleton RL. Depletion of CD8+ T cells increases susceptibility and reverses vaccine-induced immunity in mice infected with Trypanosoma cruzi. Journal of Immunology. 1990;144:717–724. [PubMed] [Google Scholar]
- Tarleton RL, Koller BH, Latour A, Postan M. Susceptibility of beta 2-microglobulin-deficient mice to Trypanosoma cruzi infection. Nature. 1992;356:338–340. doi: 10.1038/356338a0. [DOI] [PubMed] [Google Scholar]
- Tarleton RL, Sun J, Zhang L, Postan M. Depletion of T-cell subpopulations results in exacerbation of myocarditis and parasitism in experimental Chagas' disease. Infection and Immunity. 1994;62:1820–1829. doi: 10.1128/iai.62.5.1820-1829.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Torrico F, Heremans H, Rivera MT, Van Marck E, Billiau A, Carlier Y. Endogenous IFN-gamma is required for resistance to acute Trypanosoma cruzi infection in mice. Journal of Immunology. 1991;146:3626–3632. [PubMed] [Google Scholar]
- Tsuji M, Zavala F. T cells as mediators of protective immunity against liver stages of Plasmodium. Trends Parasitol. 2003;19:88–93. doi: 10.1016/s1471-4922(02)00053-3. [DOI] [PubMed] [Google Scholar]
- Ubeda JM, Legare D, Raymond F, Ouameur AA, Boisvert S, Rigault P, Corbeil J, Tremblay MJ, Olivier M, Papadopoulou B, Ouellette M. Modulation of gene expression in drug resistant Leishmania is associated with gene amplification, gene deletion and chromosome aneuploidy. Genome Biol. 2008;9:R115. doi: 10.1186/gb-2008-9-7-r115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Uzonna JE, Joyce KL, Scott P. Low dose Leishmania major promotes a transient T helper cell type 2 response that is down-regulated by interferon gamma-producing CD8+ T cells. Journal of Experimental Medicine. 2004;199:1559–1566. doi: 10.1084/jem.20040172. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Valente SA, da Costa Valente V, das Neves Pinto AY, de Jesus Barbosa Cesar M, dos Santos MP, Miranda CO, Cuervo P, Fernandes O. Analysis of an acute Chagas disease outbreak in the Brazilian Amazon: human cases, triatomines, reservoir mammals and parasites. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2009;103:291–297. doi: 10.1016/j.trstmh.2008.10.047. [DOI] [PubMed] [Google Scholar]
- Valmori D, Romero JF, Men Y, Maryanski JL, Romero P, Corradin G. Induction of a cytotoxic T cell response by co-injection of a T helper peptide and a cytotoxic T lymphocyte peptide in incomplete Freund's adjuvant (IFA): further enhancement by pre-injection of IFA alone. European Journal of Immunology. 1994;24:1458–1462. doi: 10.1002/eji.1830240633. [DOI] [PubMed] [Google Scholar]
- van der Heyde HC, Manning DD, Roopenian DC, Weidanz WP. Resolution of blood-stage malarial infections in CD8+ cell-deficient beta 2-m0/0 mice. Journal of Immunology. 1993;151:3187–3191. [PubMed] [Google Scholar]
- Villarino A, Hibbert L, Lieberman L, Wilson E, Mak T, Yoshida H, Kastelein RA, Saris C, Hunter CA. The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity. 2003;19:645–655. doi: 10.1016/s1074-7613(03)00300-5. [DOI] [PubMed] [Google Scholar]
- Vinetz JM, Kumar S, Good MF, Fowlkes BJ, Berzofsky JA, Miller LH. Adoptive transfer of CD8+ T cells from immune animals does not transfer immunity to blood stage Plasmodium yoelii malaria. Journal of Immunology. 1990;144:1069–1074. [PubMed] [Google Scholar]
- Wang R, Epstein J, Charoenvit Y, Baraceros FM, Rahardjo N, Gay T, Banania VJG, Chattopadhyay R, de la Vega P, Richie TL, et al. Induction in humans of CD8+ and CD4+ T cell and antibody responses by sequential immunization with malaria DNA and recombinant protein. Journal of Immunology. 2004;172:5561–5569. doi: 10.4049/jimmunol.172.9.5561. [DOI] [PubMed] [Google Scholar]
- Wang ZE, Reiner SL, Hatam F, Heinzel FP, Bouvier J, Turck CW, Locksley RM. Targeted activation of CD8 cells and infection of beta 2-microglobulin-deficient mice fail to confirm a primary protective role for CD8 cells in experimental leishmaniasis. Journal of Immunology. 1993;151:2077–2086. [PubMed] [Google Scholar]
- Weiss WR, Sedegah M, Beaudoin RL, Miller LH, Good MF. CD8+ T cells (cytotoxic/suppressors) are required for protection in mice immunized with malaria sporozoites. Proceedings of the National Academy of Sciences of the United States of America. 1988;85:573–576. doi: 10.1073/pnas.85.2.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Widmann C, Romero P, Maryanski JL, Corradin G, Valmori D. T helper epitopes enhance the cytotoxic response of mice immunized with MHC class I-restricted malaria peptides. Journal of Immunological Methods. 1992;155:95–99. doi: 10.1016/0022-1759(92)90275-x. [DOI] [PubMed] [Google Scholar]
- Wilkinson SR, Taylor MC, Horn D, Kelly JM, Cheeseman I. A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosomes. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:5022–5027. doi: 10.1073/pnas.0711014105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilson DC, Grotenbreg GM, Liu K, Zhao Y, Frickel EM, Gubbels MJ, Ploegh HL, Yap GS. Differential regulation of effector- and central-memory responses to Toxoplasma gondii Infection by IL-12 revealed by tracking of Tgd057-specific CD8+ T cells. PLoS Pathog. 2010;6:e1000815. doi: 10.1371/journal.ppat.1000815. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilson DC, Matthews S, Yap GS. IL-12 signaling drives CD8+ T cell IFN-gamma production and differentiation of KLRG1+ effector subpopulations during Toxoplasma gondii Infection. Journal of Immunology. 2008;180:5935–5945. doi: 10.4049/jimmunol.180.9.5935. [DOI] [PubMed] [Google Scholar]
- Wilson EB, Livingstone AM. Cutting edge: CD4+ T cell-derived IL-2 is essential for help-dependent primary CD8+ T cell responses. Journal of Immunology. 2008;181:7445–7448. doi: 10.4049/jimmunol.181.11.7445. [DOI] [PubMed] [Google Scholar]
- Wilson EH, Wille-Reece U, Dzierszinski F, Hunter CA. A critical role for IL-10 in limiting inflammation during toxoplasmic encephalitis. Journal of Neuroimmunology. 2005;165:63–74. doi: 10.1016/j.jneuroim.2005.04.018. [DOI] [PubMed] [Google Scholar]
- Wizel B, Nunes M, Tarleton RL. Identification of Trypanosoma cruzi trans-sialidase family members as targets of protective CD8+ TC1 responses. Journal of Immunology. 1997;159:6120–6130. [PubMed] [Google Scholar]
- Wizel B, Palmieri M, Mendoza C, Arana B, Sidney J, Sette A, Tarleton R. Human infection with Trypanosoma cruzi induces parasite antigen-specific cytotoxic T lymphocyte responses. Journal of Clinical Investigation. 1998;102:1062–1071. doi: 10.1172/JCI3835. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yoshida H, Hamano S, Senaldi G, Covey T, Faggioni R, Mu S, Xia M, Wakeham AC, Nishina H, Potter J, et al. WSX-1 is required for the initiation of Th1 responses and resistance to L. major infection. Immunity. 2001;15:569–578. doi: 10.1016/s1074-7613(01)00206-0. [DOI] [PubMed] [Google Scholar]
- Zhang L, Tarleton RL. Characterization of cytokine production in murine Trypanosoma cruzi infection by in situ immunocytochemistry: lack of association between susceptibility and type 2 cytokine production. European Journal of Immunology. 1996;26:102–109. doi: 10.1002/eji.1830260116. [DOI] [PubMed] [Google Scholar]
- Zhang L, Tarleton RL. Parasite persistence correlates with disease severity and localization in chronic Chagas' disease. Journal of Infectious Diseases. 1999;180:480–486. doi: 10.1086/314889. [DOI] [PubMed] [Google Scholar]