Dendritic cells (DC) and cytokines produced by DC play crucial roles in inducing and regulating pro-/anti-inflammatory and Th1/Th2 responses. DC are known to produce a Th1-pro-moting cytokine, interleukin (IL)-12, in response to malaria and other pathogenic infections, but it is thought that DC do not produce Th2-promoting cytokine, IL-4. Here, we show that a protein factor of malaria parasites induces IL-4 responses by CD11chiMHCIIhiCD3CD49bCD19FcRI DC via PI3K–Akt–NF-B signaling independent of TLR-MyD88/TRIF. Malaria parasite–activated DC induced IL-4 responses by T cells both in vitro and in vivo, favoring Th2, and il-4– deficient DC were unable to induce IL-4 expression by T cells. Interestingly, lethal parasites, Plasmodium falciparum and Plasmodium berghei ANKA, induced IL-4 response primarily by CD8 DC, whereas nonlethal Plasmodium yoelii induced IL-4 by both CD8 and CD8 DC. In both P. berghei ANKA- and P. yoelii-infected mice, IL-4 – expressing CD8 DC did not express IL-12, but a distinct CD8 DC subset expressed IL-12. In P. berghei ANKA infection, CD8 DC expressed IL-12 but not IL-4, whereas in P. yoelii infection, CD8 DC expressed IL-4 but not IL-12. These differential IL-4 and IL-12 responses by DC subsets may contribute to different Th1/Th2 development and clinical outcomes in lethal and nonlethal malaria. Our results for the first time demonstrate that a malaria protein factor induces IL-4 production by DC via PI3K–Akt–NF-B signaling, revealing signaling and molecular mechanisms that initiate and promote Th2 development.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology