CD8+ T cells remove cysts of Toxoplasma gondii from the brain mostly by recognizing epitopes commonly expressed by or cross-reactive between type II and type III strains of the parasite

Ochiai, Eri; Sa, Qila; Perkins, Sara; Grigg, Michael E.; Suzuki, Yasuhiro

doi:10.1016/j.micinf.2016.03.013

Cited by 16 publications

(16 citation statements)

References 18 publications

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“…Moreover, depletion of CD8 but not CD4 T cells impaired the ability of mice to control chronic infection. Both lineages of T cells are required to prevent reactivation in mice chronically infected with an intermediate-virulence type II strain, ME49 (39,54), and CD8 T cells are the primary effector T (T E ) cells responsible for cyst removal in this setting (41,55). Overall, our model, which uses an avirulent type III strain to generate immunological memory, is consistent with the above-mentioned models for chronic infection-and vaccineinduced immunity and positions memory CD8 T cells as central players in host resistance to T. gondii.…”

Section: Resultsmentioning

confidence: 99%

PD-L1, TIM-3, and CTLA-4 Blockade Fails To Promote Resistance to Secondary Infection with Virulent Strains of Toxoplasma gondii

et al. 2018

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T cell exhaustion is a state of hyporesponsiveness that develops during many chronic infections and cancer. Neutralization of inhibitory receptors, or 'checkpoint blockade', can reverse T cell exhaustion and lead to beneficial prognoses in experimental and clinical settings. Whether checkpoint blockade can resolve lethal acute infections is less understood, but may be beneficial in vaccination protocols that fail to elicit sterilizing immunity. Since a fully protective vaccine for any human parasite has yet to be developed, we explored the efficacy of checkpoint inhibitors in a mouse model of re-infection. Mice chronically infected with an avirulent type III strain survive reinfection with the type I RH but not MAS, GUY-DOS and GT1 parasite strains. We report here that mouse susceptibility to secondary infection correlates with initial parasite burden and that protection to the RH strain is dependent on CD8 but not CD4 T cells in this model. When given a lethal secondary infection, CD8 and CD4 T cells upregulate several co-inhibitory receptors including PD-1, TIM-3, 4-1bb and CTLA-4. Moreover, CD8 but not CD4 T cells are significantly reduced in their IFNγ response during secondary infection with virulent strains, suggesting checkpoint blockade may reduce disease severity. However, single and combination therapies targeting TIM-3, CTLA-4, and/or PD-L1 failed to reverse susceptibility to secondary infection. These results suggest that additional host responses, which are refractory to checkpoint blockade, are likely required for immunity to this pathogen.

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Section: Resultsmentioning

confidence: 99%

PD-L1, TIM-3, and CTLA-4 Blockade Fails To Promote Resistance to Secondary Infection with Virulent Strains of Toxoplasma gondii

et al. 2018

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“…Whereas our recent studies demonstrated that CD8 + immune T cells have the capability to remove the cysts from the brains of chronically infected hosts (9, 19), T. gondii antigens recognized by CD8 + T cells for the cyst removal remained unknown. The present study uncovered that GRA6Nt is a key target antigen of the protective T cells to detect the persistent stage of T. gondii for their elimination using a mouse strain genetically resistant to the infection.…”

Section: Discussionmentioning

confidence: 95%

“…2). Our recent study showed that CD8 + immune T cells remove T. gondii cysts mostly by recognizing epitopes commonly expressed in type II and III strains or cross-reactive between these two genotypes (19). Thus, the highly conserved amino acid sequence of GRA6Nt further support the possibility that GRA6Nt is a major target of CD8 + T cells for their anti-cyst protective activity.…”

Section: Discussionmentioning

confidence: 99%

“…Seven to twelve days after a transfer of CD8 + or CD8 + Vβ8.1, 8.2 + immune T cells, the brains of SCID or dm2 mice with and without the cell transfer were removed, and a half of each brain was triturated in 0.5 ml of phosphate-buffered saline (9, 19). Numbers of cysts in 3–6 aliquots (20 μl each) of the brain suspensions were counted microscopically.…”

Section: Methodsmentioning

confidence: 99%

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Determination of a Key Antigen for Immunological Intervention To Target the Latent Stage of Toxoplasma gondii

Ochiai

Tiwari

et al. 2017

The Journal of Immunology

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Toxoplasma gondii , an obligate intracellular protozoan parasite, establishes a chronic infection by forming cysts preferentially in the brain, and up to one third of human population worldwide is estimated to be chronically infected with this parasite. However, there are currently no drugs effective against the cyst form of the parasite. In addition, the protective immunity against the cysts remains largely unknown. We analyzed the molecular mechanisms by which the immune system detects host cells harboring the cysts to eliminate the latent stage of the parasite using mice with the H-2d haplotype, which are genetically resistant to the infection. Our study revealed that CD8+ immune T cells bearing T cell receptor Vβ8.1, 8.2 chain have a potent activity to remove T. gondii cysts from the brain. Our studies also uncovered that the H-2Ld is the major antigen-presenting molecule to CD8+ T cells for initiating the cyst elimination, and that the CD8+Vβ8.1, 8.2+ immune T cells recognize the amino-terminal region (amino acids 41 to 152) of dense granule protein 6 (GRA6Nt) of the parasite presented by the H-2Ld molecule. Furthermore, CD8+ immune T cells induced by immunization with recombinant GRA6Nt were eventually capable of removing the cysts from the brain when transferred to infected immunodeficient mice lacking T cells. Thus, GRA6Nt is a novel and potent antigen to activate CD8+ T cells capable of removing T. gondii cysts. These observations offer the basis for immunological intervention to combat the chronic infection with T. gondii by targeting the persistent cysts of the parasite.

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“…Upregulation of ICOS, CXCR3, CXCR6, and IL-18R in the brains of T. gondiiinfected SCID mice following a transfer of CD8 ؉ immune T cells compared to a transfer of the normal CD8 ؉ T cells. We previously demonstrated that in contrast to a transfer of CD8 ϩ immune T cells, a transfer of CD8 ϩ normal T cells from uninfected WT mice into infected SCID mice did not reduce the cyst burden in their brains within 1 week after the cell transfer (12,26). Therefore, we examined whether cerebral mRNA levels for ICOS, ICOSL, CXCR3, CXCR6, IL-18R1, and Chil3 differed between the brains of SCID mice following a transfer of CD8 ϩ immune and normal T cells from infected and uninfected WT mice, respectively, as observed between the WT and Prf1 Ϫ/Ϫ CD8 ϩ immune T cells shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Selective Upregulation of Transcripts for Six Molecules Related to T Cell Costimulation and Phagocyte Recruitment and Activation among 734 Immunity-Related Genes in the Brain during Perforin-Dependent, CD8⁺T Cell-Mediated Elimination of Toxoplasma gondii Cysts

Lutshumba

Ochiai

et al. 2020

mSystems

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We recently found that an invasion of CD8+ cytotoxic T cells into tissue cysts of Toxoplasma gondii initiates an elimination of the cysts in association with an accumulation of microglia and macrophages. In the present study, we compared mRNA levels for 734 immune-related genes in the brains of infected SCID mice that received perforin-sufficient or -deficient CD8+ immune T cells at 3 weeks after infection. At 7 days after the T cell transfer, mRNA levels for only six genes were identified to be greater in the recipients of the perforin-sufficient T cells than in the recipients of the perforin-deficient T cells. These six molecules included two T cell costimulatory molecules, inducible T cell costimulator receptor (ICOS) and its ligand (ICOSL); two chemokine receptors, C-X-C motif chemokine receptor 3 (CXCR3) and CXCR6; and two molecules related to an activation of microglia and macrophages, interleukin 18 receptor 1 (IL-18R1) and chitinase-like 3 (Chil3). Consistently, a marked reduction of cyst numbers and upregulation of ICOS, CXCR3, CXCR6, IL-18R1, and Chil3 mRNA levels were also detected when the perforin-sufficient CD8+ immune T cells were transferred to infected SCID mice at 6 weeks after infection, indicating that the CD8+ T cell-mediated protective immunity is capable of eliminating mature T. gondii cysts. These results together suggest that ICOS-ICOSL interactions are crucial for activating CD8+ cytotoxic immune T cells to initiate the destruction of T. gondii cysts and that CXCR3, CXCR6, and IL-18R are involved in recruitment and activation of microglia and macrophages to the T cell-attacked cysts for their elimination. IMPORTANCE T. gondii establishes a chronic infection by forming tissue cysts, which can grow into sizes greater than 50 μm in diameter as a consequence of containing hundreds to thousands of organisms surrounded by the cyst wall within infected cells. Our recent studies using murine models uncovered that CD8+ cytotoxic T cells penetrate into the cysts in a perforin-dependent manner and induce their elimination, which is accompanied with an accumulation of phagocytic cells to the T cell-attacked target. This is the first evidence of the ability of the T cells to invade into a large target for its elimination. However, the mechanisms involved in anticyst immunity remain unclear. Immune profiling analyses of 734 immune-related genes in the present study provided a valuable foundation to initiate elucidating detailed molecular mechanisms of the novel effector function of the immune system operated by perforin-mediated invasion of CD8+ T cells into large targets for their elimination.

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CD8+ T cells remove cysts of Toxoplasma gondii from the brain mostly by recognizing epitopes commonly expressed by or cross-reactive between type II and type III strains of the parasite

Cited by 16 publications

References 18 publications

PD-L1, TIM-3, and CTLA-4 Blockade Fails To Promote Resistance to Secondary Infection with Virulent Strains of Toxoplasma gondii

PD-L1, TIM-3, and CTLA-4 Blockade Fails To Promote Resistance to Secondary Infection with Virulent Strains of Toxoplasma gondii

Determination of a Key Antigen for Immunological Intervention To Target the Latent Stage of Toxoplasma gondii

Selective Upregulation of Transcripts for Six Molecules Related to T Cell Costimulation and Phagocyte Recruitment and Activation among 734 Immunity-Related Genes in the Brain during Perforin-Dependent, CD8⁺T Cell-Mediated Elimination of Toxoplasma gondii Cysts

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CD8+ T cells remove cysts of Toxoplasma gondii from the brain mostly by recognizing epitopes commonly expressed by or cross-reactive between type II and type III strains of the parasite

Cited by 16 publications

References 18 publications

PD-L1, TIM-3, and CTLA-4 Blockade Fails To Promote Resistance to Secondary Infection with Virulent Strains of Toxoplasma gondii

PD-L1, TIM-3, and CTLA-4 Blockade Fails To Promote Resistance to Secondary Infection with Virulent Strains of Toxoplasma gondii

Determination of a Key Antigen for Immunological Intervention To Target the Latent Stage of Toxoplasma gondii

Selective Upregulation of Transcripts for Six Molecules Related to T Cell Costimulation and Phagocyte Recruitment and Activation among 734 Immunity-Related Genes in the Brain during Perforin-Dependent, CD8+T Cell-Mediated Elimination of Toxoplasma gondii Cysts

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Selective Upregulation of Transcripts for Six Molecules Related to T Cell Costimulation and Phagocyte Recruitment and Activation among 734 Immunity-Related Genes in the Brain during Perforin-Dependent, CD8⁺T Cell-Mediated Elimination of Toxoplasma gondii Cysts