Brain microvessel cross‐presentation is a hallmark of experimental cerebral malaria

Howland, Shanshan W.; Poh, Chek Meng; Gun, Sin Yee; Claser, Carla; Malleret, Benoît; Shastri, Nilabh; Ginhoux, Florent; Grotenbreg, Gijsbert M.; Rénia, Laurent

doi:10.1002/emmm.201202273

Cited by 132 publications

(252 citation statements)

References 62 publications

Supporting

Mentioning

236

Contrasting

Order By: Relevance

“…on, this finding indicates that CD8 + T cell sequestration in the brain precedes the occurrence of CM. This observation is in agreement with a recently published study showing that there is indeed no direct correlation between the number of specific T cells in the brain and the clinical condition (40). Our results demonstrate that the reduced incidence of CM among DCIR 2/2 mice is accompanied by a decreased migration of activated CD8 + T cells into the brain compared with wild-type mice.…”

Section: Reduced CM Incidence In Dcirsupporting

confidence: 93%

“…Next, to evaluate effector functions of the brain-sequestered T cells, we determined the production of IFN-g by intracellular flow cytometry and the expression of GrB by immunohistochemistry because both have been demonstrated to be necessary for CM development (6,40,41). As a control for the immunohistochemistry staining, the expression of the endothelium marker CD31 on brain sections of PbA-infected wild-type and DCIR 2/2 mice was determined (Fig.…”

Section: Reduced CM Incidence In Dcirmentioning

confidence: 99%

See 1 more Smart Citation

The C-Type Lectin Receptor DCIR Is Crucial for the Development of Experimental Cerebral Malaria

Maglinao

Klopfleisch

Seeberger

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Cerebral malaria (CM) is the most severe complication of malaria. The murine Plasmodium berghei ANKA (PbA) infection model has helped to identify crucial players in the pathogenesis of CM. However, the role of pattern recognition receptors in innate immunity to CM induction is still poorly understood. C-type lectin receptors (CLRs) represent a family of pattern recognition receptors that recognize carbohydrate structures on pathogens and self-Ags often in a Ca2+-dependent manner. In this study, we investigated the role of the CLR dendritic cell immunoreceptor (DCIR) in the genesis of CM. Using the murine PbA infection, we show in this article that DCIR is essential for the development of CM. Although PbA infection led to 80% CM in wild-type C57BL/6 mice, DCIR-deficient mice were highly protected with only 15% CM development. In accordance with the reduced CM incidence in DCIR−/− mice, CD8+ T cell sequestration was markedly reduced in brains of PbA-infected DCIR−/− mice, which was accompanied by reduced brain inflammation. Reduced T cell sequestration in the brain was caused by decreased TNF-α levels in sera, as well as a modulated activation of CD4+ and CD8+ T cells in spleen of PbA-infected DCIR−/− mice. This study indicates that DCIR is critically involved in CM induction, thus highlighting the importance of this CLR in innate immunity during malaria infection.

show abstract

Section: Reduced CM Incidence In Dcirsupporting

confidence: 93%

Section: Reduced CM Incidence In Dcirmentioning

confidence: 99%

The C-Type Lectin Receptor DCIR Is Crucial for the Development of Experimental Cerebral Malaria

Maglinao

Klopfleisch

Seeberger

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The methods for generating T cell receptor (TCR)-transduced reporter cell lines were described by us previously (19). In short, brain-sequestered CD8 ϩ lymphocytes were isolated, sorted, and subjected to TCR sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…Malaria-specific CD8 ϩ T cells were found in the brains of ECM-susceptible mice during infection (17,18). We recently reported the discovery of the D b -restricted epitope SQLLNAKYL (named Pb1) from glideosome-associated protein 50 and demonstrated that Pb1-specific CD8 ϩ T cells are sequestered in the brains of infected mice, are highly cytolytic, and are capable of damaging the blood-brain barrier (19). Brain microvessels from PbA-infected mice cross-presented the Pb1 epitope when mice started to exhibit neurological signs, supporting the hypothesis that CD8 ϩ T cells attack the microvasculature in an antigen-specific manner.…”

mentioning

confidence: 99%

Damage to the Blood-Brain Barrier during Experimental Cerebral Malaria Results from Synergistic Effects of CD8⁺T Cells with Different Specificities

2014

Self Cite

View full text Add to dashboard Cite

c CD8؉ T cells play a pathogenic role in the development of murine experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA) infection in C57BL/6 mice. Only a limited number of CD8 ؉ epitopes have been described. Here, we report the identification of a new epitope from the bergheilysin protein recognized by PbA-specific CD8 ؉ T cells. Induction and functionality of these specific CD8 ؉ T cells were investigated in parallel with previously reported epitopes, using new tools such as tetramers and reporter cell lines that were developed for this study. We demonstrate that CD8 ؉ T cells of diverse specificities induced during PbA infection share many characteristics. They express cytolytic markers (gamma interferon [IFN-␥], granzyme B) and chemokine receptors (CXCR3, CCR5) and damage the blood-brain barrier in vivo. Our earlier finding that brain microvessels in mice infected with PbA, but not with non-ECM-causing strains, cross-presented a shared epitope was generalizable to these additional epitopes. Suppressing the induction of specific CD8؉ T cells through tolerization with a high-dose peptide injection was unable to confer protection against ECM, suggesting that CD8 ؉ T cells of other specificities participate in this process. The tools that we developed can be used to further investigate the heterogeneity of CD8 ؉ T cell responses that are involved in ECM. Malaria remains a global threat to humanity, claiming approximately 700,000 lives annually, with children under 5 years old making up the large majority of fatal cases (1). Cerebral malaria (CM) is the most devastating and deadly complication of Plasmodium falciparum infection, and mortality remains significant even with artesunate treatment (2). As ethical constraints limit the study of this complication in humans, mouse models in which mice susceptible to experimental cerebral malaria (ECM) display many characteristics that closely resemble the human pathology were developed (3-5). In ECM-susceptible C57BL/6J mice, infection with Plasmodium berghei ANKA (PbA), but not P. yoelii 17XNL (Py17XNL) or P. berghei NK65 (PbNK65), results in the accumulation of parasitized red blood cells (RBCs) in the brain microvasculature (6, 7) and other deep organs, leukocyte accumulation, blood-brain barrier (BBB) disruption, and hemorrhages (reviewed in reference 8).ECM mouse models have helped to uncover some of the mechanisms underlying the immunopathogenesis of this neuropathology. The T cell arm of the immune system plays an essential role in ECM development. CD4 ϩ T cell involvement is restricted mostly to the earlier phase of induction, while CD8 ϩ T cells are the principal pathogenic effectors since their depletion just before neurological symptoms manifest prevents ECM (9, 10). The inflammatory molecules IFN-␥, granzyme B, and perforin were also found to be essential, as mice deficient in these molecules do not succumb to this disease (11-13). By piecing together these and other findings in the literature, a model of ECM pathogenesis in which CD8 ϩ...

show abstract

“…Although we cannot comment as to epitope specificity of these CD8 + T cells, we assume that they are specific to pre-erythrocytic parasite Ag. The Ag specificity of T cells that migrate to the brain in ECM is still mostly undescribed, although a recent publication identified one conserved CD8 epitope cross-presented by the brain microvessels (5). Although it is attractive to speculate that a shared antigenic repertoire may exist between the parasitized hepatocyte and the infected erythrocyte, and is displayed via MHCI on the cytokine-activated brain endothelial cell (62), it is conceivable that CD8 + T cell-mediated protection leading to NCM is not restricted to any one particular Ag.…”

Section: Cd11cmentioning

confidence: 99%

Chemical Attenuation of Plasmodium in the Liver Modulates Severe Malaria Disease Progression

Lewis

Behrends

Cunha

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Cerebral malaria is one of the most severe complications of malaria disease, attributed to a complicated series of immune reactions in the host. The syndrome is marked by inflammatory immune responses, margination of leukocytes, and parasitized erythrocytes in cerebral vessels leading to breakdown of the blood–brain barrier. We show that chemical attenuation of the parasite at the very early, clinically silent liver stage suppresses parasite development, delays the time until parasites establish blood-stage infection, and provokes an altered host immune response, modifying immunopathogenesis and protecting from cerebral disease. The early response is proinflammatory and cell mediated, with increased T cell activation in the liver and spleen, and greater numbers of effector T cells, cytokine-secreting T cells, and proliferating, proinflammatory cytokine-producing T cells. Dendritic cell numbers, T cell activation, and infiltration of CD8+ T cells to the brain are decreased later in infection, possibly mediated by the anti-inflammatory cytokine IL-10. Strikingly, protection can be transferred to naive animals by adoptive transfer of lymphocytes from the spleen at very early times of infection. Our data suggest that a subpopulation belonging to CD8+ T cells as early as day 2 postinfection is responsible for protection. These data indicate that liver stage–directed early immune responses can moderate the overall downstream host immune response and modulate severe malaria outcome.

show abstract

Brain microvessel cross‐presentation is a hallmark of experimental cerebral malaria

Cited by 132 publications

References 62 publications

The C-Type Lectin Receptor DCIR Is Crucial for the Development of Experimental Cerebral Malaria

The C-Type Lectin Receptor DCIR Is Crucial for the Development of Experimental Cerebral Malaria

Damage to the Blood-Brain Barrier during Experimental Cerebral Malaria Results from Synergistic Effects of CD8⁺T Cells with Different Specificities

Chemical Attenuation of Plasmodium in the Liver Modulates Severe Malaria Disease Progression

Contact Info

Product

Resources

About

Brain microvessel cross‐presentation is a hallmark of experimental cerebral malaria

Cited by 132 publications

References 62 publications

The C-Type Lectin Receptor DCIR Is Crucial for the Development of Experimental Cerebral Malaria

The C-Type Lectin Receptor DCIR Is Crucial for the Development of Experimental Cerebral Malaria

Damage to the Blood-Brain Barrier during Experimental Cerebral Malaria Results from Synergistic Effects of CD8+T Cells with Different Specificities

Chemical Attenuation of Plasmodium in the Liver Modulates Severe Malaria Disease Progression

Contact Info

Product

Resources

About

Damage to the Blood-Brain Barrier during Experimental Cerebral Malaria Results from Synergistic Effects of CD8⁺T Cells with Different Specificities