Removal of Toxoplasma gondii Cysts from the Brain by Perforin-Mediated Activity of CD8+ T Cells

Suzuki, Yasuhiro; Wang, Xisheng; Jortner, Benard S.; Payne, Laura Beth; Ni, Yanyan; Michie, Sara A.; Xu, Baohui; Kudo, Tadashi; Perkins, Sara

doi:10.2353/ajpath.2010.090825

Cited by 115 publications

(183 citation statements)

References 41 publications

(24 reference statements)

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“…Although adoptive transfer of perforin-deficient CD8 ϩ T cells is effective at preventing TE, recent work supports the model of cytolytic cyst control, as transferred IFN-␥-deficient CD8 ϩ T cells are able to greatly reduce cyst burden in a chronic reactivation model (44). The multifaceted effects of IFN-␥ on the immune system make it difficult to separate the contribution of CD8 ϩ T cell IFN-␥ from that of other sources of this cytokine.…”

Section: Ifn-␥-producing Cells: From T To Nk Cells and Neutrophilsmentioning

confidence: 95%

Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

2014

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Toxoplasma gondii is an obligate intracellular parasite of clinical importance, especially in immunocompromised patients. Investigations into the immune response to the parasite found that T cells are the primary effector cells regulating gamma interferon (IFN-␥)-mediated host resistance. However, recent studies have revealed a critical role for the innate immune system in mediating host defense independently of the T cell responses to the parasite. This body of knowledge is put into perspective by the unifying theme that immunity to the protozoan parasite requires a strong IFN-␥ host response. In the following review, we discuss the role of IFN-␥-producing cells and the signals that regulate IFN-␥ production during T. gondii infection.

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Section: Ifn-␥-producing Cells: From T To Nk Cells and Neutrophilsmentioning

confidence: 95%

Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

2014

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“…The latent stage is associated with marginal inflammation and cell recruitment to the CNS, which is necessary to provide adequate IFN-g levels, the major driving force for parasite control. In the murine models of chronic infection, the characteristics of T cell subsets (24,(63)(64)(65), specific mononuclear cells, for example, resident microglia and APCs, have been extensively studied. In contrast, the role of the newly described myeloid cell subsets is controversial and thus requires further investigation (19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

“…Despite limited access, the CNS is inundated by immune cells from the periphery during the chronic stage of T. gondii infection. The adaptive immune responses in the CNS have been extensively investigated, describing an important contribution to the local parasite control (22)(23)(24)(25). Besides, several studies have highlighted the function and phenotype of certain mononuclear cells such as microglia, brain DCs, and macrophages upon cerebral toxoplasmosis; however, the role of recruited newly described myeloid cell subpopulations remains undefined (19,26,27).…”

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confidence: 99%

Ly6Chigh Monocytes Control Cerebral Toxoplasmosis

Biswas

Bruder

Wolf

et al. 2015

The Journal of Immunology

100

125

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Cerebral infection with the parasite Toxoplasma gondii is followed by activation of resident cells and recruitment of immune cells from the periphery to the CNS. In this study, we show that a subset of myeloid cells, namely Ly6ChighCCR2+ inflammatory monocytes that infiltrate the brain upon chronic T. gondii infection, plays a decisive role in host defense. Depletion of this monocyte subset resulted in elevated parasite load and decreased survival of infected mice, suggesting their crucial role. Notably, Ly6ChighCCR2+ monocytes governed parasite control due to production of proinflammatory mediators, such as IL-1α, IL-1β, IL-6, inducible NO synthase, TNF, and reactive oxygen intermediate. Interestingly, Ly6ChighCCR2+ monocytes were also able to produce the regulatory cytokine IL-10, revealing their dual feature. Moreover, we confirmed by adoptive transfer that the recruited monocytes further develop into two distinct subpopulations contributing to parasite control and profound host defense. The differentiated Ly6CintCCR2+F4/80int subset upregulated MHC I and MHC II molecules, suggesting dendritic cell properties such as interaction with T cells, whereas the Ly6CnegF4/80high cell subset displayed elevated phagocytic capacity while upregulating triggering receptor expressed on myeloid cells-2. Finally, we have shown that the recruitment of Ly6Chigh monocytes to the CNS is regulated by P-selectin glycoprotein ligand-1. These results indicate the critical importance of recruited Ly6Chigh monocytes upon cerebral toxoplasmosis and reveal the behavior of further differentiated myeloid-derived mononuclear cell subsets in parasite control and immune regulation of the CNS.

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“…As mentioned earlier, previous studies in chronic T. gondii model have demonstrated that cytotoxicity and, especially, IFN-␥ production are critical effector mechanisms for CD8 ϩ T cell-mediated parasite control (15,37,44). The differential contributions of these effector mechanisms to short-term parasite control by donor CD8 ϩ T cells need to be assessed.…”

Section: Cd8mentioning

confidence: 99%

Donor CD8⁺T Cells Prevent Toxoplasma gondii De-Encystation but Fail To Rescue the Exhausted Endogenous CD8⁺T Cell Population

2013

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Functional exhaustion of CD8؉ T cells due to increased expression of inhibitory molecule PD-1 (Programmed Death-1) causes reactivation of latent disease during later phases of chronic toxoplasmosis. Onset of disease recrudescence results in decreased parasite cyst burden concomitant with parasites undergoing stage conversion from a primarily encysted, quiescent bradyzoite to a fast-replicating, highly motile tachyzoite. Thus, reduced cyst burden is one of the early hallmarks of disease recrudescence. This was further validated by depleting gamma interferon (IFN-␥), a cytokine known to control latent toxoplasmosis, in chronically infected prerecrudescent mice. Since CD8 ؉ T cells (an important source of IFN-␥) lose their functionality during the later phases of chronic toxoplasmosis, we next examined if adoptive transfer of functional CD8 ؉ T cells from acutely infected donors to the chronically infected prerecrudescent hosts could impede parasite de-encystation and rescue exhausted CD8 ؉ T cells. While the transfer of immune CD8؉ T cells temporarily restricted the breakdown of cysts, the exhausted endogenous CD8 ؉ T cell population was not rescued. Over time, the donor population got deleted, resulting in parasite de-encystation and host mortality. Considering that donor CD8 ؉ T cells fail to become long-lived, one of the cardinal features of memory CD8 ؉ T cells, it bears the implication that memory CD8 differentiation is impaired during chronic toxoplasmosis. Moreover, our data strongly suggest that while adoptive immunotherapy can prevent parasite de-encystation transiently, reduced antigen burden in the chronic phase by itself is insufficient for rescue of exhausted CD8 ؉ T cells. The conclusions of this study have profound ramifications in designing immunotherapeutics against chronic toxoplasmosis.

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Removal of Toxoplasma gondii Cysts from the Brain by Perforin-Mediated Activity of CD8+ T Cells

Cited by 115 publications

References 41 publications

Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

Ly6Chigh Monocytes Control Cerebral Toxoplasmosis

Donor CD8⁺T Cells Prevent Toxoplasma gondii De-Encystation but Fail To Rescue the Exhausted Endogenous CD8⁺T Cell Population

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Removal of Toxoplasma gondii Cysts from the Brain by Perforin-Mediated Activity of CD8+ T Cells

Cited by 115 publications

References 41 publications

Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

Ly6Chigh Monocytes Control Cerebral Toxoplasmosis

Donor CD8+T Cells Prevent Toxoplasma gondii De-Encystation but Fail To Rescue the Exhausted Endogenous CD8+T Cell Population

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Product

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Donor CD8⁺T Cells Prevent Toxoplasma gondii De-Encystation but Fail To Rescue the Exhausted Endogenous CD8⁺T Cell Population