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Toxoplasma gondii , an apicomplexan parasite, is a pathogenic protozoan that can infect the central nervous system. In pregnant women, infection can result in congenital problems of the fetus, while in immunocompromised individual it can lead to severe neurological consequences. Although CD8 T cells play an important effector role in controlling the chronic infection, their maintenance is dependent on the critical help provided by CD4 T cells. In a recent study, we demonstrated that reactivation of the infection in chronically infected host is a consequence of CD8 T dysfunction caused by CD4 T cell exhaustion. Furthermore, treatment of chronically infected host with antigen-specific non-exhausted CD4 T cells can restore CD8 T cell functionality and prevent reactivation of the latent infection. The exhaustion status of CD4 T cells is mediated by the increased expression of the transcription factor BLIMP-1, and deletion of this molecule led to the restoration of CD4 T cell function, reversal of CD8 exhaustion and prevention of reactivation of the latent infection. In a recent study from our laboratory, we also observed an increased expression of miR146a levels by CD4 T cells from the chronically infected animals. Recent reports have demonstrated that microRNAs (especially miR146a) has a strong impact on the immune system of T. gondii infected host. Whether these molecules have any role in the BLIMP-1 up-regulation and dysfunctionality of these cells needs to be investigated. [ABSTRACT FROM AUTHOR]

CD8 T cells are important for maintaining the chronicity of Toxoplasma gondii infection. In a T. gondii encephalitis susceptible model, we recently demonstrated that CD4 T cells play an essential helper role in the maintenance of the effector response and CD8 T cell dysfunctionality was linked to CD4 T cell exhaustion. However, CD4 T cells are constituted of different subsets with various functions and the population(s) providing help to the CD8 T cells has not yet been determined. In the present study, T follicular helper cells (Tfh), which are known to be essential for B cell maturation and are one of the main sources of IL-21, were significantly increased during chronic toxoplasmosis. However, at week 7 p.i., when CD8 T cells are exhausted, the Tfh population exhibited increased expression of several inhibitory receptors and levels of IL-21 in the serum were decreased. The importance of IL-21 in the maintenance of CD8 T cells function after T. gondii infection was further demonstrated in IL-21R KO mouse model. Interestingly, while CD8 T cells from both knockout (KO) and wild-type mice expressed similar levels of PD-1, animals with defective IL-21 signaling exhibited lower polyfunctionality than wild-type controls. This reduced polyfunctional ability observed in CD8 T cells from KO mice was associated with a significant increase in other inhibitory receptors like Tim-3, LAG-3, and 2B4. Furthermore, the animals exhibited greater signs of Toxoplasma reactivation manifested by the reduced number of cysts and increased expression of tachyzoite (replicative form of the parasite) specific genes (SAG1 and ENO2) in the brain. Also, IL-21R KO mice displayed a higher frequency of tachyzoite-infected monocytes in the blood and spleen. Our findings suggest the importance of Tfh and IL-21 during chronic toxoplasmosis and establish a critical role for this cytokine in regulating CD8 T cell dysfunction by preventing the co-expression of multiple inhibitory receptors during chronic parasitic infection. [ABSTRACT FROM AUTHOR]

Vaccine-mediated immunity to parasites has not been achieved. Immune C57BL/6 mice are susceptible to secondary Toxoplasma gondii infection. Using a forward genetics approach, Souza et al. identify Nfkbid as an important factor for the regulation of B cell immunity during secondary Toxoplasma infection and protection against rechallenge. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii is an obligate intracellular parasite that can cause severe complications in the newborn and immunocompromised individuals. The parasite evokes a strong innate immune response in the infected hosts which is followed by a robust adaptive immunity. In the last few years, importance of innate immune mechanisms dependent on the role of MyD-88 independent pathways, inflammatory monocytes and innate lymphocyte have been identified. However, notwithstanding the strong immune response to the parasite, the chronic infection persists in the host. The inability to prevent chronic infection can be attributed to aberration in the memory CD8 T cell response caused by an increased expression of inhibitory receptors that leads to their dysfunctionality. • Toxoplasma gondii evokes a strong innate and adaptive immune response in the host. • Innate immunity to the parasite is comprised of many components like DC, neutrophils, macrophages, inflammatory monocytes, and NK cells. • CD4 T cells (Toxoplasmic encephalitis) play an important helper role in the maintenance of long-term CD8 T cell immunity. • CD8 T cells (Toxoplasmic encephalitis) control chronic infection by IFNg and cytotoxic activity. • In an encephalitis model of infection, CD8 T cells undergo exhaustion due to increased expression of inhibitory receptors. [ABSTRACT FROM AUTHOR]

Abstract: Long-term protection against Toxoplasma gondii is dependent on robust CD8+ T cell immunity. In the absence of this response, the host is unable to maintain chronicity, which results in recrudescence of infection and possible death. Factors needed for the persistence of protective CD8+ T cells against the parasite need to be evaluated. Previous studies from our laboratory have reported that synergism between γ chain cytokines like IL-7 and IL-15 is critical for the generation of CD8+ T cell response needed for protection during acute infection. In this study we report that the situation is different during the recall response where CD8+ T cell response is almost entirely dependent on IL-15, with IL-7 at best playing a minor role. In the absence of IL-15, CD8+ T cells fail to respond optimally to parasitic re-challenge and hosts are unable to control their replication, which leads to their death. Thus T. gondii infection may represent a unique situation where CD8+ T cell response during secondary challenge is primarily dependent on IL-15 with other γ chain cytokines having nominal effect. These findings provide important information regarding factors involved in the generation of protective immunity against T. gondii with strong implications in developing immunotherapeutic agents against the pathogen. [Copyright &y& Elsevier]

The article discusses CD8 T cells exhaustion during chronic toxoplasmosis and its implication for immunotherapy against Toxoplasma gondii protozoa. Based on observation, HIV-infected nonprogressors is controlled by virus-specific polyfunctional CD8 T cell response and development of memory phenotype CD44 and CD127. A study is cited which explored the positive costimulatory signals CD40-CD40L pathway during the rescue of exhausted C8 T cells.

In this study, we document that Toxoplasma gondii differentiation and reactivation are mediated by systemic CD8 1-cell dysfunction during chronic infection. We demonstrate that CD8+ 1-cell exhaustion occurs despite control of parasitemia during early-chronic toxoplasmosis. During later phases, these cells become exhausted, leading to parasite reactivation and mortality. Concomitant with increased CD8+ T-cell apoptosis and decreased effector response, this dysfunction is characterized by a graded elevation in expression of inhibitory receptor PD-1 on these cells in both lymphoid and nonlymphoid tissue.. Blockade of the PD-1-PDL-1 pathway reinvigorates this suboptimal CD8+ T-cell response, resulting in control of parasite reactivation and prevention of mortality in chronically infected animals. To the best of our knowledge, this report is unique in showing that exposure to a persistent pathogen despite initial control of parasitemia can lead to CD8+ t-cell dysfunction and parasite reactivation. [ABSTRACT FROM AUTHOR]

CD8 T cells are essential for control of Toxoplasma gondii infection. Once activated they undergo differentiation into short-lived effector and memory precursor effector cells. As effector cells, CD8 T cells exert immune pressure on the parasite via production of inflammatory cytokines and through their cytolytic activity. Once immune control has been established, the parasite encysts and develops into chronic infection regulated by the memory CD8 T-cell population. Several signals are needed for this process to be initiated and for development of fully differentiated memory CD8 T cells. With newly developed tools including CD8 Tcell tetramers and TCR transgenic mice, dissecting the biology behind T. gondii-specific CD8 T-cell responses can now be more effectively addressed. In this paper, we discuss what is known about the signals required for effective T. gondii-specific CD8 T-cell development, their differentiation, and effector function. [ABSTRACT FROM AUTHOR]

CD8+ T cells play an essential role in the protection against both acute as well as chronic Toxoplasma gondii infection. Although the role of IL-15 has been reported to be important for the development of long-term CD8+ T cell immunity against the pathogen, the simultaneous roles played by both IL-15 and related c-chain family cytokine IL-7 in the generation of this response during acute phase of infection has not been described. We demonstrate that while lack of IL-7 or IL-15 alone has minimal impact on splenic CD8+ T cell maturation or effector function development during acute Toxoplasmosis, absence of both IL-7 and IL-15 only in the context of infection severely down-regulates the development of a potent CD8+ T cell response. This impairment is characterized by reduction in CD44 expression, IFN-γ production, proliferation and cytotoxicity. However, attenuated maturation and decreased effector functions in these mice are essentially downstream consequences of reduced number of antigen-specific CD8+ T cells. Interestingly, the absence of both cytokines did not impair initial CD8+ T cell generation but affected their survival and differentiation into memory phenotype IL-7Rahi cells. Significantly lack of both cytokines severely affected expression of Bcl-2, an anti-apoptotic protein, but minimally affected proliferation. The overarching role played by these cytokines in eliciting a potent CD8+ T cell immunity against T. gondii infection is further evidenced by poor survival and high parasite burden in anti IL-7 treated IL-152/2 mice. These studies demonstrate that the two cytokines, IL-7 and IL-15, are exclusively important for the development of protective CD8+ T cell immune response against T. gondii. To the best of our knowledge this synergism between IL-7 and IL-15 in generating an optimal CD8+ T cell immunity against intracellular parasite or any other infectious disease model has not been previously reported. [ABSTRACT FROM AUTHOR]

IFN-γ-producing CD4+ T cells, although important for protection against acute Toxoplasma gondii infection, can cause gut pathology, which may prove to be detrimental for host survival. Here we show that mice lacking IL-15 gene develop a down-regulated IFN-γ-producing CD4+ T cell response against the parasite, which leads to a reduction in gut necrosis and increased level of survival against infection. Moreover, transfer of immune CD4+ T cells from WT to IL-15-/- mice reversed inhibition of gut pathology and caused mortality equivalent to levels of parental WT mice. Down-regulated CD4+ T cell response in the absence of IL-15, manifested as reduced antigen-specific proliferation, was due to defective priming of the T cell subset by dendritic cells (DCs) of these animals. When stimulated with antigen-pulsed DCs from WT mice, CD4+ T cells from IL-15-/- mice were primed optimally, and robust proliferation of these cells was observed. A defect in the DCs of knockout mice was further confirmed by their reduced ability to produce IL-12 upon stimulation with Toxoplasma lysate antigen. Addition of exogenous IL-15 to DC cultures from knockout mice led to increased IL-12 production by these cells and restored their ability to prime an optimal parasite-specific CD4+ T cell response. To our knowledge, this is the first demonstration of the role of IL-15 in the development of CD4+ T cell immunity against an intracellular pathogen. Furthermore, based on these observations, targeting of IL-15 should have a beneficial effect on individuals suffering from CD4+ T cell-mediated autoimmune diseases. [ABSTRACT FROM AUTHOR]

We have developed a murine model to investigate the pathogenesis of acquired ocular toxoplasmosis. Tachyzoites of PLK strain of Toxoplasma gondii were intracamerally inoculated under anesthesia into the right eyes of naive or perorally preinfected C57BL/6 and MRL-MpJ mice. Clinical and histopathological observations of responses to intraocular infection were analyzed. Ocular inflammation from Toxoplasma gondii is dose-dependent in both strains of mice. After inoculation of fifty parasites, no evidence of inflammation was observed in the eyes of naive mice. The eyes of naive mice that received 500 or 5,000 parasites developed inflammatory changes by day 6 post challenge. By day 8, the changes progressed to moderate to severe intraocular inflammation. Histologic analysis of the ocular lesions demonstrated mononuclear cell infiltration and necrosis predominantly in the anterior segment of the eyes of the naive mice. Inoculation of 50,000 tachyzoites induced a destructive ocular inflammatory response and was uniformly lethal to the mice by approximately one week after challenge. In contrast, eyes from mice previously orally infected with Toxoplasma gondii and that received a 50 or 500 parasite intracameral challenge revealed no inflammation, but the eyes receiving 5,000 parasites demonstrated necrotic focal retinochoroiditis with vitreitis by day 8 after challenge. The murine model reproduces some features of ocular toxoplasmosis in humans and may be suitable for large-scale controlled studies of the pathogenesis and therapeutics of acquired ocular toxoplasmosis as well as for study of the mechanisms of immune privilege in the eye. [ABSTRACT FROM AUTHOR]

Presents information pertaining to the dichotomous role for nitric oxide as it relates to the acute Toxoplasma gondii infection in mice. Indication of findings; Recognition of the importance of cytokines in host resistance against infection with Toxoplasma gondii; What role does the cytokines play; Susceptibility of mice towards acute T. gondii.

Infection of mice with Toxoplasma gondii has been shown to induce a transient state of immune down-regulation. Earlier reports have demonstrated the role of cytokines, in particular IL-10, in this host response. Here evidence is presented that T.gondll, a major opportunistic pathogen of the newborn and those with AIDS, is able to induce CD4+ T cell population Increased in volume by day 7 post-infection and expressed T cell maturation markers (CD44hl, Il-2rhl,Mel-14fo). Further noted was a clonal activation of several CD4+ T cells subsets expressing the Vβ chain of the TCR. At day 7 post-infection, partial reduction of all CD4+ T cells to mltogen or parasite antigen stimulation was observed, In particular Vβ5 T cells. Addition of rlL-2 partially restored the CD4+ T cell proliferative response in Vitro. The T cell activation marker CTLA-4 could not be detected and te co-stimulatory molecule, CD28, was down-regulated. Elctrophonetic and morphologic analysis of these cells post0culture demostrated a DNA fragmentation pattern and cell death consistent with apoptosis. These studies demonstrate for the first time in a protozoan parasite that activation-induced CD4+ T cell unresponslveness occurs during actue T.gondll Infection in mice, and may be important in immune down-regulation and parasite persistence in the infected host.0 [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are considered to be essential for the initiation of immune responses against pathogens. Although myeloid differentiation factor 88 an adaptor molecule for most TLRs, is important for protection against Toxoplasma gondii, the TLR responsible for eliciting an immune response against this obligate intracellular pathogen remains unknown. A recent article reports that mice lacking TLR9 cannot develop severe inflammatory responses to T. gondii infection. The implications of this finding are discussed here. [Copyright &y& Elsevier]

Protozoan parasites cause severe morbidity and mortality in humans worldwide, especially in developing countries where access to chemotherapeutic agents is limited. Although parasites initially evoke a robust immune response, subsequent immunity fails to clear infection, ultimately leading to the chronic stage. This enigmatic situation was initially addressed in chronic viral models, where T cells lose their function, a phenomenon referred to as ‘exhaustion’. However, recent studies demonstrate that this paradigm can be extended to protozoan diseases as well, although with notable differences. These studies have revealed that T cell responses generated against Toxoplasma gondii, Plasmodium sp., and Leishmania sp. can become dysfunctional. This review discusses T cell exhaustion in parasitic infection, mechanisms of development, and a possible role in disease outcome. [ABSTRACT FROM AUTHOR]