Pathogenic T cells in cerebral malaria

Rénia, Laurent; Potter, Sarah M.; Mauduit, Marjorie; Rosa, Daniela Santoro; Kayibanda, Michèle; Deschemin, Jean-Christophe; Snounou, Georges; Grüner, Anne Charlotte

doi:10.1016/j.ijpara.2006.02.007

Cited by 104 publications

(112 citation statements)

References 65 publications

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“…In accordance, we report a 2.9-fold reduction in the number of CD4 + T cells that express IFN-g + in Tbx21 2/2 mice during the induction phase (day 3) of disease (Fig. 8D), when CD4 + T cells are known to exert a pathogenic effect (2). In contrast, the frequency of IFN-g + CD8 + T cells was not reduced in Tbx21 2/2 mice.…”

Section: Figuresupporting

confidence: 87%

“…T cells have been shown to play an important role in the immunopathogenesis of ECM (1,2). In the Pb2A C57BL/6 model, CD4 + T cells mediate the induction phase of immunopathogenesis of ECM, whereas CD8 + T cells mediate the effector phase of disease (3) by perforin and granzyme-dependent apoptosis of brain endothelial cells (4)(5)(6).…”

Section: Erebral Malaria (Cm) Remains a Major Cause Of Death Inmentioning

confidence: 99%

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The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

Oakley

Sahu

Lotspeich-Cole

et al. 2013

The Journal of Immunology

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The pathogenesis of experimental cerebral malaria (ECM) is an immunologic process, mediated in part by Th1 CD4+ T cells. However, the role of the Th1 CD4+ T cell differentiation program on the ability to control parasitemia and susceptibility to ECM disease during blood stage malaria has never been assessed directly. Using the Plasmodium berghei ANKA murine model of ECM and mice deficient for the transcription factor T-bet (the master regulator of Th1 cells) on the susceptible C57BL/6 background, we demonstrate that although T-bet plays a role in the regulation of parasite burden, it also promotes the pathogenesis of ECM. T-bet−deficient (Tbx21−/−) mice had higher parasitemia than wild type controls did during the ECM phase of disease (17.7 ± 3.1% versus 10.9 ± 1.5%). In addition, although 100% (10/10) of wild type mice developed ECM by day 9 after infection, only 30% (3/10) of Tbx21−/− mice succumbed to disease during the cerebral phase of infection. Resistance to ECM in Tbx21−/− mice was associated with diminished numbers of IFN-γ–producing CD4+ T cells in the spleen and a lower accumulation of CD4+ and CD8+ T cells in the brain. An augmented Th2 immune response characterized by enhanced production of activated GATA-3+ CD4+ T cells and elevated levels of the eotaxin, MCP-1, and G-CSF cytokines was observed in the absence of T-bet. Our results suggest that in virulent malarias, immune modulation or therapy resulting in an early shift toward a Th2 response may help to ameliorate the most severe consequences of malaria immunopathogenesis and the prospect of host survival.

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Section: Figuresupporting

confidence: 87%

Section: Erebral Malaria (Cm) Remains a Major Cause Of Death Inmentioning

confidence: 99%

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

Oakley

Sahu

Lotspeich-Cole

et al. 2013

The Journal of Immunology

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“…29 CD8 ϩ T cells are the primary effector cells of CM in the PbA mouse model, although their precise mechanism of action is not known. 8 PKC-is expressed in T cells and is a key component of T-cell receptor signaling and activation. 12,13,33,34 However, PKC--dependent pathways are differently required in T-cell activation and are especially critical for development of Th2 but not Th1 cells.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Fauconnier

Bourigault

Même

et al. 2011

The American Journal of Pathology

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Cerebral malaria is the most severe neurologic complication in children and young adults infected with Plasmodium falciparum. T-cell activation is required for development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (CM). To characterize the T-cell activation pathway involved, the role of protein kinase C-theta (PKC-) in experimental CM development was examined. PKC--deficient mice are resistant to CM development. In the absence of PKC-, no neurologic sign of CM developed after blood stage PbA infection. Resistance of PKC--deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and magnetic resonance angiography, whereas wild-type mice developed distinct microvascular pathology. Recruitment and activation of CD8 ؉ T cells, and ICAM-1 and CD69 expression were reduced in the brain of resistant mice; however, the pulmonary inflammation and edema associated with PbA infection were still present in the absence of functional PKC-. Resistant PKC--deficient mice developed high parasitemia, and died at 3 weeks with severe anemia. Therefore, PKC-signaling is crucial for recruitment of CD8 ؉ T cells and development of brain microvascular pathology resulting in fatal experimental CM, and may represent a novel therapeutic target of CM.

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“…We hypothesized that regulatory mechanisms, which safe-guard against over-exuberant adaptive immune responses, hamper CD4 1 T-cell-dependent parasite control and have tested this hypothesis in an experimental model of cerebral malaria (ECM) caused by infection of C57BL/6 mice with Plasmodium berghei ANKA (PbA). CD8 1 T cells are known to mediate immune pathology in the brain in this model [18][19][20][21][22][23], but the roles of CD4 1 T cells have not been clearly defined. Although they contribute to disease pathogenesis [22,24,25], it is unclear whether CD4 1 T cells acquire any capacity to control parasites.…”

Section: Introductionmentioning

confidence: 93%

Type I interferons suppress CD4⁺ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

et al. 2011

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During blood‐stage Plasmodium infection, large‐scale invasion of RBCs often occurs before the generation of cellular immune responses. In Plasmodium berghei ANKA (PbA)‐infected C57BL/6 mice, CD4+ T cells controlled parasite numbers poorly, instead providing early help to pathogenic CD8+ T cells. Expression analysis revealed that the transcriptional signature of CD4+ T cells from PbA‐infected mice was dominated by type I IFN (IFN‐I) and IFN‐γ‐signalling pathway‐related genes. A role for IFN‐I during blood‐stage Plasmodium infection had yet to be established. Here, we observed IFN‐α protein production in the spleen of PbA‐infected C57BL/6 mice over the first 2 days of infection. Mice deficient in IFN‐I signalling had reduced parasite burdens, and displayed none of the fatal neurological symptoms associated with PbA infection. IFN‐I substantially inhibited CD4+ T‐bet+ T‐cell‐derived IFN‐γ production, and prevented this emerging Th1 response from controlling parasites. Experiments using BM chimeric mice revealed that IFN‐I signalled predominantly via radio‐sensitive, haematopoietic cells, but did not suppress CD4+ T cells via direct signalling to this cell type. Finally, we found that IFN‐I suppressed IFN‐γ production, and hampered efficient control of parasitaemia in mice infected with non‐lethal Plasmodium chabaudi. Thus, we have elucidated a novel regulatory pathway in primary blood‐stage Plasmodium infection that suppresses CD4+ T‐cell‐mediated parasite control.

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Pathogenic T cells in cerebral malaria

Cited by 104 publications

References 65 publications

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Type I interferons suppress CD4⁺ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

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Pathogenic T cells in cerebral malaria

Cited by 104 publications

References 65 publications

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Type I interferons suppress CD4+ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

Contact Info

Product

Resources

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Type I interferons suppress CD4⁺ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection