부산대학교 도서관

Immunity against malaria depends on germinal center (GC)-derived antibody responses that are orchestrated by T follicular helper (TFH) cells. Emerging data show that the regulatory cytokine IL-10 plays an essential role in promoting GC B cell responses during both experimental malaria and virus infections. Here we investigated the cellular source and temporal role of IL-10, and whether IL-10 additionally signals to CD4 T-cells to support anti-Plasmodium humoral immunity. Distinct from reports of virus infection, we found that IL-10 expressed by conventional, Foxp3-negative effector CD4 T cells and functioned in a B cell-intrinsic manner only during the first 96 hours of Plasmodium infection to support humoral immunity. The critical functions of IL-10 manifested only before the orchestration of GC responses and were primarily localized outside of B cell follicles. Mechanistically, our studies showed that the rapid and transient provision of IL-10 promoted B cell expression of anti-apoptotic factors, MHC class II, CD83, and cell-cell adhesion proteins that are essential for B cell survival and interaction with CD4 T cells. Together, our data reveal temporal features and mechanisms by which IL-10 critically supports humoral immunity during blood-stage Plasmodium infection, information that may be useful for developing new strategies designed to lessen the burden of malaria. Author summary: Malaria is associated with the expression of both inflammatory and anti-inflammatory cytokines that together regulate disease severity and the function of parasite-specific immune cells subsets. Emerging data show that the anti-inflammatory cytokine Interleukin (IL)-10 can function to sustain an already established humoral immune response during acute and chronic virus infections. Unexpectedly, our results show that IL-10 functions only within the first 72–96 hours of Plasmodium blood-stage infection to promote initial helper T cell and B cell interactions, as well as B cell differentiation and survival. Our studies of the temporal features, spatial relationships, critical cellular sources and mechanisms by which IL-10 promotes humoral immunity during malaria highlight the distinct mechanisms governing anti-malarial immunity. This new information may lead to the identification of novel pathways and approaches for eliciting durable protection against malaria. [ABSTRACT FROM AUTHOR]