A Role for Natural Regulatory T Cells in the Pathogenesis of Experimental Cerebral Malaria

Amante, Fiona H.; Stanley, Amanda C.; Randall, Louise M.; Zhou, Yonghong; Haque, Ashraful; McSweeney, Karli M.; Waters, Andrew P.; Janse, Chris J.; Good, Michael F.; Hill, Geoffrey R.; Engwerda, Christian

doi:10.2353/ajpath.2007.061033

Cited by 160 publications

(190 citation statements)

References 60 publications

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“…Transgenic PbA (clone: 231c1l) constitutively expressing luciferase and GFP from the EF1-a promoter (PbA-luc) was used for all PbA experiments, unless stated otherwise [24,53]. Transgenic PbA strains expressing model T-cell epitopes (PbTG) and control strains (PbG) were obtained from Professor William R. Heath (University of Melbourne, Australia) and maintained and used as previously reported [28].…”

Section: Methodsmentioning

confidence: 99%

“…Blood, spleen and brain mononuclear cells were prepared as previously described [24,29,53]. Allophycocyanin or Pacific Blue (PB)-conjugated anti-TCRb chain (H57-597), phycoerythrin (PE)-Cy5-or PE-conjugated anti-CD4 (GK1.5), PE-Cy5-conjugated anti-CD8a (53-6.7), PE or fluorescein isothiocyanate-conjugated anti-CD45.1 (A20), allophycocyanin or PE-conjugated anti-IFN-g (XMG1.2), and PE-conjugated anti-IL-10 (JES5-16E3), anti-IL-17A (TC11-18H10) were purchased from Biolegend (San Diego, CA, USA) or BD Biosciences (Franklin Lakes, NJ, USA).…”

Section: Flow Cytometry and Antibody-mediated Depletion/ Blockadementioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Flow Cytometry and Antibody-mediated Depletion/ Blockadementioning

confidence: 99%

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

et al. 2011

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“…Regulatory T cells can be beneficial or detrimental to the induction of ECM depending on the method and timing of regulatory T cell depletion and the genetic background of the host (17)(18)(19)(20)(21)(22)(23)(24). Th17 cells, which induce tissue inflammation and are capable of disrupting the blood brain barrier (25), do not appear to contribute to the pathogenesis of ECM (26).…”

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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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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“…In naive mice, CD4 ϩ Foxp3 ϩ T cells express CD25. Thus, Abs against CD25 have been used to deplete CD4 ϩ CD25 ϩ T reg (14,15). Although this approach has provided novel information on the function of T reg , it is problematic because depletion is not complete in several organs (16) and may also interfere with activated T effector cells (T eff ) expressing CD25, as recently shown during chronic Toxoplasma gondii infection (17).…”

mentioning

confidence: 99%

Limited Role of CD4+Foxp3+ Regulatory T Cells in the Control of Experimental Cerebral Malaria

Steeg

Adler

Sparwasser

et al. 2009

The Journal of Immunology

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Cerebral malaria (CM) associated with Plasmodium berghei ANKA (PbA) infection is an accepted model of human CM. CM during PbA infection critically depends on sequestration of T cells into the brain. Several studies aimed to address the role of regulatory T cells (Treg) in modulating this pathogenic T cell response. However, these studies are principally hampered due to the fact that until recently no reagents were available to deplete Foxp3+ Treg specifically. To study the function of Treg in the genesis of CM, we used depletion of Treg mice that are transgenic for a bacterial artificial chromosome expressing a diphtheria toxin receptor-enhanced GFP fusion protein under the control of the foxp3 gene locus. These mice allow for a selective depletion of Foxp3+ Treg by diphtheria toxin injection, and also their specific detection and purification during an ongoing infection. Using depletion of Treg mice, we found only a small increase in the absolute numbers of Foxp3+ Treg during PbA infection and, consequently, the ratio of Treg to T effector cells (Teff) decreased due to the rapid expansion of Teff. Although the latter sequester in the brains of infected mice, almost no Treg were found in the brains of infected mice. Furthermore, we demonstrate that depletion of Treg has no influence on sequestration of Teff and on the clinical outcome, and only minor influence on T cell activation. Using ex vivo analysis of purified Treg from either naive mice or PbA-infected mice, we found that both exhibit similar inhibitory capacity on Teff.

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A Role for Natural Regulatory T Cells in the Pathogenesis of Experimental Cerebral Malaria

Cited by 160 publications

References 60 publications

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

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

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

Limited Role of CD4+Foxp3+ Regulatory T Cells in the Control of Experimental Cerebral Malaria

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A Role for Natural Regulatory T Cells in the Pathogenesis of Experimental Cerebral Malaria

Cited by 160 publications

References 60 publications

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

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

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

Limited Role of CD4+Foxp3+ Regulatory T Cells in the Control of Experimental Cerebral Malaria

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

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