Importance of distinct dendritic cell subsets in malaria immunity and pathology
Date of Issue2014
School of Biological Sciences
Plasmodium species infections trigger strong innate and acquired immune responses, which are often associated with severe pathology, like in the case of cerebral malaria. Dendritic cells (DCs), a heterogeneous family of antigen presenting cells, constitute the most important myeloid lineage in orchestrating the host immune responses against the parasite. However, due to the cellular complexity of the innate immune system, the contribution of distinct DC subsets has remained elusive. In order to untangle the roles of different DC subsets in protection against Plasmodium parasites and in parasite induced pathology, we have generated three independent mouse strains (Siglec-H-, Clec9A- and Clec4a4-DTR mice) which allow us to specifically ablate in vivo plasmacytoid DCs, CD8+Clec9A+ and CD8−CD11b+ DCs, respectively. The aim of this thesis was to study the consequences of the absence of these myeloid cell subtypes during blood stage malaria, using the murine P. yoelii and P. berghei ANKA experimental models. In infection with a P. yoelii 17X clone 1.1 non lethal strain, DT treatment of both Siglec-H- and Clec9A-DTR strains resulted in an improved control and clearance of the parasite, whereas Clec4a4 DTR mice did not control parasite growth and succumbed to infection after 12 to 16 days. When compared to Siglec-H-, Clec4a4-DTR and wild type (wt) mice, Clec9A-DTR mice had significantly reduced serum levels of the Th1 cytokine Interferon gamma (IFN-γ). Consistently, ablation of Clec9A+ DCs resulted in a switching towards Th2 immune responses and in the generation of a clear isotype profile of parasite-specific antibodies (IgG1 > IgG2a). When injected intra peritoneally, these IgG1 antibodies reduced blood levels of non lethal P. yoelii, however did not protect mice when infected with a lethal strain. The higher susceptibility of the Clec4a4-DTR mice to the non lethal P. yoelii strain could possibly be explained by the lack of F4/80+ red pulp macrophages which, together with the CD8−CD11b+ DCs, are also affected upon DT injection. Using the P. berghei ANKA mouse model of experimental cerebral malaria, we have shown that the Clec9A+ subset, but not the Clec4a4+ subset, of conventional DCs, are the antigen presenting cells responsible for priming and activating cytotoxic CD8+ T cells involved in ECM pathogenesis. All of these findings contribute to a better understanding of malaria immunity and pathology, and point the way for future investigations, which might lead to new applications in vaccine development and malaria immunotherapy.