Control of pathogenic CD8⁺ T cell migration to the brain by IFN‐γ during experimental cerebral malaria

Abstract

Previous studies have shown that IFN-gamma is essential for the pathogenesis of cerebral malaria (CM) induced by Plasmodium berghei ANKA (PbA) in mice. However, the exact role of IFN-gamma in the pathway (s) leading to CM has not yet been described. Here, we used 129P2Sv/ev mice which develop CM between 7 and 14 days post-infection with PbA. In this strain, both CD4(+) and CD8(+) T cells were involved in the effector phase of CM. When 129P2Sv/ev mice deficient in the IFN-gamma receptor alpha chain (IFN-gammaR1) were infected with PbA, CM did not occur. Migration of leucocytes to the brain at the time of CM was observed in wild type (WT) but not in deficient mice. However, in the latter, there was an accumulation of T cells in the lungs. Analysis of chemokines and their receptors in WT and in deficient mice revealed a complex, organ-specific pattern of expression. Up-regulation of RANTES/CCL5, IP-10/CCL3 and CCR2 was associated with leucocyte migration to the brain and increased expression of MCP-1/CCL2, IP-10/CCL3 and CCR5 with leucocyte migration to the lung. This shows that IFN-gamma controls trafficking of pathogenic T cells in the brain, thus providing an explanation for the organ-specific pathology induced by PbA infection.

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

“…Decreases in inflammatory markers have been associated with protection from ECM (41), which suggests that reduced levels of IFNγ observed with FTY720 and LX2931 treatment may have contributed to increased survival (Figure 4; Supplemental Figure 1). …”

“…Importantly in the context of ECM, FTY720 can cross the BBB and be phosphorylated within the CNS (24). Since S1P receptors are expressed on all cell types found within the CNS (25), FTY720 can restrict immune cell entry into the CNS (39) and could contribute to reduced CM pathology by limiting lymphocyte infiltration into the brain (40), a process implicated in ECM pathogenesis (41). We show that lymphocyte infiltration (both CD4 + and CD8 + cells) in the brain is decreased in mice treated with FTY720 1 d before infection and 1 d p.i.…”

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

“…Studies depleting IFN-g (10) or using IFN-g2 deficient mice (43) have demonstrated that IFN-g is a critical mediator of ECM in susceptible strains of mice. In addition, IFNgR2deficient mice have been shown to be resistant to ECM, and this resistance is associated with reduced levels of CD8 + T cells in the brain (37). Importantly, a recent study indicates that the major source of IFN-g that modulates ECM pathogenesis is CD4 + T cells (38).…”

Cannabinoid Receptor 2 Modulates Susceptibility to Experimental Cerebral Malaria through a CCL17-dependent Mechanism

“…The reduced 18S RNA in the presence of a comparable parasitemia in Cnr2 Ϫ/Ϫ versus WT mice indicates a reduction in parasite sequestration in the brain (25). We therefore investigated the integrity of the blood-brain-barrier (BBB) by assessing the diffusion of Evans Blue into the brain (1,2). In contrast to WT mice, infected Cnr2 Ϫ/Ϫ brains displayed a reduced Evans Blue staining, indicative of an attenuated BBB disruption (Fig.…”