Immune CD8+ T cells prevent reactivation of Toxoplasma gondii infection in the immunocompromised host (original) (raw)
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Infection and Immunity, 2002
T-cell immunity is critical for survival of hosts infected with Toxoplasma gondii. Among the cells in the T-cell population, CD8 ؉ T cells are considered the major effector cells against this parasite. It is believed that CD4 ؉ T cells may be crucial for induction of the CD8 ؉ -T-cell response against T. gondii. In the present study, CD4 ؊/؊ mice were used to evaluate the role of conventional CD4 ؉ T cells in the immune response against T. gondii infection. CD4 ؊/؊ mice infected with T. gondii exhibited lower gamma interferon (IFN-␥) messages in the majority of their tissues. As a result, mortality due to a hyperinflammatory response was prevented in these animals. Interestingly, T. gondii infection induced a normal antigen-specific CD8 ؉ -T-cell immune response in CD4 ؊/؊ mice. No difference in generation of precursor cytotoxic T lymphocytes (pCTL) or in IFN-␥ production by the CD8 ؉ -T-cell populations from the knockout and wild-type animals was observed. However, the mutant mice were not able to sustain CD8 ؉ -T-cell immunity. At 180 days after infection, the CD8 ؉ -T-cell response in the knockout mice was depressed, as determined by pCTL and IFN-␥ assays. Loss of CD8 ؉ -T-cell immunity at this time was confirmed by adoptive transfer experiments. Purified CD8 ؉ T cells from CD4 ؊/؊ donors that had been immunized 180 days earlier failed to protect the recipient mice against a lethal infection. Our study demonstrated that although CD8 ؉ -T-cell immunity can be induced in the absence of conventional CD4 ؉ T cells, it cannot be maintained without such cells.
The FASEB Journal, 2013
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.
Infection and Immunity, 2013
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.
CD8 T Cells and Toxoplasma gondii: A New Paradigm
Journal of Parasitology Research, 2011
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.
The Journal of Immunology
C57BL/6 mice chronically infected with an avirulent strain (ME-49) of Toxoplasma gondii were used to study the mechanisms by which T lymphocytes and IFN-gamma prevent reactivation of latent infection. Infected animals were treated with mAb, either anti-CD8, anti-CD4, anti-CD4 plus anti-CD8, anti-IFN-gamma, or anti-CD4 plus anti-IFN-gamma and the mice followed for survival, histopathology, cyst numbers, and spleen cell cytokine responses. In agreement with previously published findings, treatment with anti-IFN-gamma antibodies fully reactivated the asymptomatic infection, inducing massive necrotic areas in the brain with the appearance of free tachyzoites and death of all animals within 2 wk. Mice treated with the combination of anti-CD4 plus anti-CD8 antibodies showed augmented pathology and mortality nearly identical to the anti-IFN-gamma- treated animals. In contrast, treatment with anti-CD4 or anti-CD8 mAb alone failed to result in significantly enhanced brain pathology or mortal...
Infection and Immunity, 2005
CD8 ؉ T-cell immunity plays an important role in protection against intracellular infections. Earlier studies have shown that CD4 ؉ T-cell help was needed for launching in vivo CD8 ؉ T-cell activity against these pathogens and tumors. However, recently CD4 ؉ T-cell-independent CD8 responses during several microbial infections including those with Toxoplasma gondii have been described, although the mechanism is not understood. We now demonstrate that, in the absence of CD4 ؉ T cells, T. gondii-infected mice exhibit an extended NK cell response, which is mediated by continued interleukin-12 (IL-12) secretion. This prolonged NK cell response is critical for priming parasite-specific CD8 ؉ T-cell immunity.
Shaping Successful and Unsuccessful CD8 T Cell Responses Following Infection
Journal of Biomedicine and Biotechnology, 2010
CD8 T cells play a vital role in the immunological protection against intracellular pathogens. Ideally, robust effector responses are induced, which eradicate the pathogen, and durable memory CD8 T cells are also established, which help confer protection against subsequent reinfection. The quality and magnitude of these responses is dictated by multiple factors, including their initial interactions with professional antigen-presenting cells, as well as the cytokine milieu and availability of CD4 T cell help. These factors set the transcriptional landscape of the responding T cells, which in turn influences their phenotypic and functional attributes as well as ultimate fate. Under certain conditions, such as during chronic infections, the development of these usually successful responses becomes subverted. Here we discuss advances in our understanding of the cellular and molecular determinants of T cell quality, and the formation of effector, memory, and exhausted CD8 T cells, during acute and chronic infections.
PLoS ONE, 2010
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-c 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-7Ra hi 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-15 2/2 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.
Characteristics and critical function of CD8+ T cells in the Toxoplasma-infected brain
The rise of the AIDS epidemic made the requirement for T cells in our continuous protection from pathogens critically apparent. The striking frequency with which AIDS patients exhibited profound neurological pathologies brought attention to many chronic infections that are latent within the immune-privileged CNS. One of the most common lethal opportunistic infections of these patients was with the protozoan parasite, Toxoplasma gondii. Reactivation of Toxoplasma cysts within the brain causes massive tissue destruction evidenced as multiple ring-enhancing lesions on MRI and is called toxoplasmic encephalitis (TE). TE is not limited to AIDS patients, but rather is a risk for all severely immunocompromised patients, including recipients of chemotherapy or transplant recipients. The lessons learned from these patient populations are supported by T cell depletion studies in mice. Such experiments have demonstrated that CD4+ and CD8+ T cells are required for protection against TE. Although it is clear that these T cell subsets work synergistically to fight infection, much evidence has been generated that suggests CD8+ T cells play a dominant role in protection during chronic toxoplasmosis. In other models of CNS inflammation, such as intracerebral infection with LCMV and experimental autoimmune encephalomyelitis (EAE), infiltration of T cells into the brain is harmful and even fatal. In the brain of the immunocompetent host, the well-regulated T cell response to T. gondii is therefore an ideal model to understand a controlled inflammatory response to CNS infection. This review will examine our current understanding of CD8+ T cells in the CNS during T. gondii infection in regards to the (1) mechanisms governing entry into the brain, (2) cues that dictate behavior within the brain, and (3) the functional and phenotypic properties exhibited by these cells.