Neuropilin-1-dependent modulation of T cell responses during blood-stage and experimental cerebral malaria

Neuropilin-1 (Nrp-1) is a co-receptor for VEGF, semaphorins as well as TGF-β and plays a role in neuronal development and angiogenesis. It is expressed by various cells, including tumour and endothelial cells, but also immune cells, where it seems to be involved in the activation of T cells. In addition, a previous study of our research group showed that regulatory T cells (Tregs) migrate into tumour tissue via the Nrp-1/VEGF axis and influence the anti-tumour immune response. In the present study, Nrp-1 expression was analysed in the context of blood-stage malaria. The characterisation of Plasmodium yoelii (PY)-infected Balb/c mice showed a significant increase of Nrp-1 on CD4+FoxP3- effector T cells, which are the main actors in parasite clearance in this model, besides B cells. These Nrp-1+CD4+ T cells showed a highly activated phenotype, which was reduced during PY infection of T cell-specific Nrp-1-ablated Nrp-1fl/fl x CD4cretg mice without affecting the parasitic load. In an experimental model of cerebral malaria (ECM), the impact of Nrp-1 expression on activation as well as migration of T cells was analysed in Plasmodium berghei ANKA (PbA)-infected C57BL/6 mice. During PbA infection, CD8+ T cells are the main pathology-driving cells, as they migrate from the spleen to the brain and induce a disruption of the blood-brain barrier leading to neuroinflammation. It is striking that CD8+ T cells, which normally express very low frequencies of Nrp-1, significantly upregulated Nrp-1 during ECM. Microarray and flow cytometric analyses revealed a highly activated phenotype of Nrp-1+CD8+ T cells. In fact, Nrp-1 expression on CD8+ T cells correlated with the severity of ECM pathology. PbA-infected mice with a T cell-specific ablation of Nrp-1 showed significantly reduced numbers of cytotoxic T cells in the brain compared to wildtype littermates. Consequently, ablation of Nrp-1 in Nrp-1fl/fl x CD4cretg mice resulted in improved ECM pathology. The blockade of the Nrp-1-VEGF interaction was negligible during PbA ...