Development of a Novel CD4 TCR Transgenic Line That Reveals a Dominant Role for CD8 Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria.

We describe an MHC class II (I-A)-restricted TCR transgenic mouse line that produces CD4 T cells specific for species. This line, termed PbT-II, was derived from a CD4 T cell hybridoma generated to blood-stage ANKA (PbA). PbT-II cells responded to all species and stages tested so far, including rodent (PbA, NK65, AS, and 17XNL) and human () blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8 T cell-mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4 T cells and the previously described PbT-I CD8 T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8 DC (a subset of XCR1 DC) were the major APC responsible for activation of both T cell subsets, although other DC also contributed to CD4 T cell responses. Depletion of CD8 DC at the beginning of infection prevented ECM development and impaired both Th1 and follicular Th cell responses; in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4 T cell immunity during malaria and provides evidence that CD4 T cell help, acting via CD40L signaling, can promote immunity or pathology to blood-stage malaria largely through Ag presentation by CD8 DC.