A Th1 response is required for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The role of pro-Th1 IL-12 in malaria is complex and controversial. In this study, we addressed the role of IL-12Rβ2 in ECM development. C57BL/6 mice deficient for IL-12Rβ2, IL-12p40, or IL-12p35 were analyzed for ECM development after blood-stage PbA infection in terms of ischemia and blood flow by noninvasive magnetic resonance imaging and angiography, T cell recruitment, and gene expression. Without IL-12Rβ2, no neurologic sign of ECM developed upon PbA infection. Although wild-type mice developed distinct brain microvascular pathology, ECM-resistant, IL-12Rβ2–deficient mice showed unaltered cerebral microcirculation and the absence of ischemia after PbA infection. In contrast, mice deficient for IL-12p40 or IL-12p35 were sensitive to ECM development. The resistance of IL-12Rβ2–deficient mice to ECM correlated with reduced recruitment of activated T cells and impaired overexpression of lymphotoxin-α, TNF-α, and IFN-γ in the brain after PbA infection. Therefore, IL-12Rβ2 signaling is essential for ECM development but independent from IL-12p40 and IL-12p35. We document a novel link between IL-12Rβ2 and lymphotoxin-α, TNF-α, and IFN-γ expression, key cytokines for ECM pathogenesis.

Cerebral malaria is a severe complication ofEur. J. Immunol. 2013Immunol. . 43: 2683Immunol. -2695 Plasmodium falciparum-infected children and young adults [1]. Cerebral malaria pathophysiology is still poorly understood, combining cerebral vascular obstruction, and exacerbated immune responses. Indeed, investigations in humans and mice documented the sequestration of erythrocytes, parasitized or not, platelets and leucocytes in cerebral blood vessels with an increased proinflammatory cytokine expression [1][2][3]. The specific role of T cells in cerebral malaria pathogenesis has been difficult to address in humans. In mice however, T-cell sequestration and activation in the brain are crucial steps for experimental cerebral malaria (ECM) development after Plasmodium berghei ANKA (PbA) infection [4][5][6][7]. In particular, αβ-CD8 + T cells sequestrated in the brain play a pathogenic, effector role for ECM development [6], and we showed recently a role for protein kinase C-θ (PKC-θ) in PbAinduced ECM pathogenesis [8]. Besides being a critical regulator of TCR signaling and T-cell activation, PKC-θ is involved in interferon type I/II signaling in human T cells [9]. Type II IFN-γ is essential for PbA-induced ECM development [10][11][12], promoting CD8 + T-cell accumulation in the brain [7,[12][13][14]. Type IIFNs are induced during viral infection but they also contribute to the antibacterial immune response. ResultsThe IFN-γ pathway is essential for ECM development upon sporozoite PbA infectionThe IFN-γ pathway is central for ECM development after bloodstage PbA infection. We first assessed the role of this pathway in preerythrocytic/intrahepatic stage infection by investigating ECM neurological signs development in IFN-γR1 −/− mice. Following the injection of 1000 sporozoites, 60% of the WT control mice developed typical ECM neurological symptoms, such as ataxia, loss of grip strength, progressive paralysis, and coma, and succumbed within 8-9 days, as previously described [22]. In contrast, IFN-γR1 −/− mice were fully resistant to the same challenge, surviving 30 days with no ECM neurological signs (Fig. 1A). Therefore, type II IFN-γ pathway is essential for ECM development after PbA sporozoite infection.Hampered ECM development in the absence of IFN-α/β pathway upon hepatic or blood-stage PbA infectionThe role of type I IFN-α/β versus type II IFN-γ pathways in ECM development after infection with hepatic or blood-stage PbA was then assessed in mice deficient for either IFNAR1 or IFN-γR1. IFNAR1 −/− mice were partially protected against ECM following sporozoite-initiated infection, only 20% dying before day 10, and 40% eventually developing typical ECM neurological symptoms, which reflected a delayed ECM development after infection with sporozoites ( Fig. 1A), as compared with WT control mice, 60% of which developed ECM and died before day 10, and IFN-γR1-deficient mice, which were fully resistant to PbA challenge. After injection of PbA-parasited red blood cells (10 5 pRBC/ mouse), WT mice succumbed within 7-...