On the Pathogenic Role of Brain-Sequestered αβ CD8+ T Cells in Experimental Cerebral Malaria

Abstract

Cerebral malaria (CM) develops in a small proportion of persons infected with Plasmodium falciparum and accounts for a substantial proportion of the mortality due to this parasite. The actual pathogenic mechanisms are still poorly understood, and in humans investigations of experimental CM are unethical. Using an established Plasmodium berghei-mouse CM model, we have investigated the role of host immune cells at the pathological site, the brain. We report in this study the detailed quantification and characterization of cells, which migrated and sequestered to the brain of mice with CM. We demonstrated that CD8+ αβ T cells, which sequester in the brain at the time when neurological symptoms appear, were responsible for CM mortality. These observations suggest a mechanism which unifies disparate observations in humans.

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

“…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.…”

“…We also examined CD8 1 T-cell responses in IFN-aR1 À/À mice, since these cells are crucial for end stage pathology in this model [21,22,25]. CD8 1 T-cell recruitment to the brain and their expression of GzmB (Fig.…”

Rôle de l’histamine et des récepteurs histaminiques dans la pathogenèse du paludisme

“…La résistance des souris HDC -/-vis-à-vis du parasite Pb ANKA est clairement associée à la préservation de la BHE contrairement aux souris C57BL/6 qui présentent une rupture de la BHE associée à une séquestration de globules rouges infectés dans le cerveau de celles-ci [24] ( Figure 1). Une des caractéristiques du neuropaludisme chez la souris est la séques-tration des lymphocytes T CD4 + et CD8 + dans les microvaisseaux sanguins du cerveau [27,28]. Cela a été confirmé par nos résultats qui montrent une augmentation significative des lymphocytes T CD4 + et CD8 + dans le cerveau des souris C57BL/6 infectées par Pb ANKA.…”

Involvement of CD8+ T cells in protective immunity against murine blood‐stage infection with Plasmodium yoelii 17XL strain

“…However, there are some reports in murine models that CD8 1 T cells contribute to the pathology of experimental cerebral malaria. Mice that are depleted in, or do not have, CD8 1 T cells, are protected against experimental cerebral malaria [13]. CD8 1 T cells might contribute via perforin (PFN)-dependent destruction of cerebral microvasculor endothelial cells [14].…”