A malaria protein factor induces IL-4 expression by dendritic cells via TLR/MyD88-independent signaling, promoting Th2 development

Abstract Dendritic cells (DCs) and cytokines produced by DCs play crucial roles in inducing and regulating pro/anti-inflammatory and Th1/Th2 responses. While DCs are known to produce Th1-promoting IL-12 in response to malaria and other pathogenic infections, it is widely thought that DCs do not produce Th2-promoting IL-4. Here, we show that a protein factor of malaria parasites induces IL-4 responses by CD11chiMHCIIhiCD3ɛ−CD49b−CD19− FcɛRI− DCs via MyD88-independent signaling. Malaria parasite-activated wild type DCs induced IL-4 responses by T cells. Interestingly, lethal parasites, Plasmodium falciparum and P. berghei ANKA, induced IL-4 response primarily by CD8α− DCs, whereas nonlethal P. yoelii induced IL-4 by both CD8α+ and CD8α− DCs. In both P. Berghei ANKA- and P. yoelii-infected mice, IL-4-expressing CD8α− DCs did not express IL-12 and a distinct population expressed IL-12. Further, in P berghei ANKA-infection, CD8α+ DCs expressed IL-12 but not IL-4, whereas in P. yoelii infection CD8α+ DCs expressed IL-4 but not IL-12. This differential IL-4 and IL-12 responses by DC subpopulations may contribute to differential Th1 and Th2 development and different clinical outcomes in lethal and nonlethal malaria. Our results for the first time demonstrated that a malaria protein factor induces IL-4 production by DCs, revealing the molecular mechanism that initiate the promotes Th2 development.