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.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Its pathogenesis is frequently linked to liver inflammation. Gain-of-function mutations in the gene encoding β-catenin are frequent genetic modifications found in human HCCs. Thus, we investigated whether inflammation was a component of β-catenin-induced tumorigenesis using genetically modified mouse models that recapitulated the stages of initiation and progression of this tumoral process. Oncogenic β-catenin signaling was found to induce an inflammatory program in hepatocytes that involved direct transcriptional control by β-catenin and activation of the NF-κB pathway. This led to a specific inflammatory response, the intensity of which determined the degree of tumor aggressiveness. The chemokine-like chemotactic factor leukocyte cell-derived chemotaxin 2 (LECT2) and invariant NKT (iNKT) cells were identified as key interconnected effectors of liver β-catenin-induced inflammation. In genetic deletion models lacking the gene encoding LECT2 or iNKT cells, hepatic β-catenin signaling triggered the formation of highly malignant HCCs with lung metastasis. Thus, our results identify inflammation as a key player in β-catenin-induced liver tumorigenesis. We provide strong evidence that, by activating pro-and antiinflammatory mediators, β-catenin signaling produces an inflammatory microenvironment that has an impact on tumoral development. Our data are consistent with the fact that most β-catenin-activated HCCs are of better prognosis.