The capacity of splenic CD11c+ dendritic cell (DC) populations to present antigen (Ag) to T cells differs during malarial infection with Plasmodium chabaudi in mice. Both CD11c+CD8+ and CD8− DCs presented malarial peptides on their surface during infection. However, although both DC subsets expressing malaria peptides could induce interferon-γ production by CD4 T cells, only CD8− DCs isolated at the acute phase of infection stimulated Ag-specific T cell proliferation and interleukin (IL)-4 and -10 production from MSP1-specific T cell receptor for Ag transgenic T cells coincidental with our reported Th1 to Th2 switch at this stage in response to the pathogen. The timing of these distinct DC responses coincided with increased levels of apoptosis in the CD8+ population and an increase in the numbers of CD8− DCs in the spleen. Our data suggest that the switch in CD4 T cell responses observed in P. chabaudi–infected mice may be the result of the presentation by different DC populations modified by the malaria infection.

Host responses controlling blood-stage malaria include both innate and acquired immune effector mechanisms. During Plasmodium chabaudi infection in mice, a population of CD11b(high)Ly6C(+) monocytes are generated in bone marrow, most of which depend on the chemokine receptor CCR2 for migration from bone marrow to the spleen. In the absence of this receptor mice harbor higher parasitemias. Most importantly, splenic CD11b(high)Ly6C(+) cells from P chabaudi-infected wild-type mice significantly reduce acute-stage parasitemia in CCR2(-/-) mice. The CD11b(high)Ly6C(+) cells in this malaria infection display effector functions such as production of inducible nitric oxide synthase and reactive oxygen intermediates, and phagocytose P chabaudi parasites in vitro, and in a proportion of the cells, in vivo in the spleen, suggesting possible mechanisms of parasite killing. In contrast to monocyte-derived dendritic cells, CD11b(high)Ly6C(+) cells isolated from malaria-infected mice express low levels of major histocompatibility complex II and have limited ability to present the P chabaudi antigen, merozoite surface protein-1, to specific T-cell receptor transgenic CD4 T cells and fail to activate these T cells. We propose that these monocytes, which are rapidly produced in the bone marrow as part of the early defense mechanism against invading pathogens, are important for controlling blood-stage malaria parasites.

We recently reported that splenic dendritic cells (DC) in rats can be separated into CD4+ and CD4− subsets and that the CD4− subset exhibited a natural cytotoxic activity in vitro against tumor cells. Moreover, a recent report suggests that CD4− DC could have tolerogenic properties in vivo. In this study, we have analyzed the phenotype and in vitro T cell stimulatory activity of freshly isolated splenic DC subsets. Unlike the CD4− subset, CD4+ splenic DC expressed CD5, CD90, and signal regulatory protein α molecules. Both fresh CD4− and CD4+ DC displayed an immature phenotype, although CD4+ cells constitutively expressed moderate levels of CD80. The half-life of the CD4−, but not CD4+ DC in vitro was extremely short but cells could be rescued from death by CD40 ligand, IL-3, or GM-CSF. The CD4− DC produced large amounts of the proinflammatory cytokines IL-12 and TNF-α and induced Th1 responses in allogeneic CD4+ T cells, whereas the CD4+ DC produced low amounts of IL-12 and no TNF-α, but induced Th1 and Th2 responses. As compared with the CD4+ DC that strongly stimulated the proliferation of purified CD8+ T cells, the CD4− DC exhibited a poor CD8+ T cell stimulatory capacity that was substantially increased by CD40 stimulation. Therefore, as previously shown in mice and humans, we have identified the existence of a high IL-12-producing DC subset in the rat that induces Th1 responses. The fact that both the CD4+ and CD4− DC subsets produced low amounts of IFN-α upon viral infection suggests that they are not related to plasmacytoid DC.

Dendritic cells (DCs) are a rare population of leukocytes specialized in Ag processing and presentation to T cells. We have previously shown that cultured rat splenic DCs exhibit a cytotoxic activity against selected target cells. In this study, we analyzed this function in DCs freshly prepared from lymphoid organs using the DC-specific OX62 mAb and magnetic beads. Freshly extracted splenic DCs, but not lymph node and thymic DCs, exhibited a strong and moderate cytotoxic activity against YAC-1 and K562 target cells, respectively. FACS analyses showed that spleen contained a minor subset (10–15%) of CD4+ and class IIint DCs that also expressed the OX41 Ag and the lymphoid-related Ags CD5 and CD90 (Thy-1) and a major (80–85%) subset of CD4−/OX41−/CD5− and class IIint DCs. The cytotoxic activity of splenic DCs was strictly restricted to the CD4− DCs, a subset poorly represented in LN and thymus. Contrasting with our previous report using cultured splenic DCs, freshly isolated splenic DCs killed YAC-1 cells using a Ca2+-independent mechanism, but this function did not appear mediated by Fas ligand, TNF-related apoptosis-inducing ligand, or TNF-α. Therefore, rat DCs contain a subset of naturally cytolytic cells that could play a role in both innate and acquired immune responses. Together with our previous report, these data suggest that rat DCs can use two mechanisms of cytotoxicity depending on their maturation/activation state.