No abstract

Dendritic cells (DCs) play a crucial role in the immune responses against infections by sensing microbial invasion through toll-like receptors (TLRs). In humans, two distinct DC subsets, CD11c− plasmacytoid DCs (PDCs) and CD11c+ myeloid DCs (MDCs), have been identified and can respond to different TLR ligands, depending on the differential expression of cognate TLRs. In this study, we have examined the effect of TLR-7 ligands on human DC subsets. Both subsets expressed TLR-7 and could respond to TLR-7 ligands, which enhanced the survival of the subsets and upregulated the surface expression of costimulatory molecules such as CD40, CD80, and CD86. However, the cytokine induction pattern was distinct in that PDCs and MDCs produced interferon (IFN)-α and interleukin (IL)-12, respectively. In response to TLR-7 ligands, the Th1 cell supporting ability of both DC subsets was enhanced, depending on the cytokines the respective subsets produced. This study demonstrates that TLR-7 exerts its biological effect in a DC subset-specific manner.

Based on the relative expression of CD11c and CD1a, we previously identified subsets of dendritic cells (DCs) or DC precursors in human peripheral blood. A CD1a+/CD11c+ population (CD11c+ DCs), also called myeloid DCs, is an immediate precursor of Langerhans cells, whereas a CD1a−/CD11c− population (CD11c− DCs), sometimes called lymphoid DCs but better known as plasmacytoid DCs, is composed of type I IFN (IFN-αβ)-producing cells. Here, we investigate the effects of IFN-αβ and IFN-γ as well as other cytokines on CD11c+ and CD11c− DC subsets, directly isolated from the peripheral blood, instead of in vitro-generated DCs. IFN-γ and IFN-α, rather than GM-CSF, were the most potent cytokines for enhancing the maturation of CD11c+ DCs. Incubation of CD11c+ DCs with IFN-γ also resulted in increased IL-12 production, and this IL-12 allowed DCs to increase Th1 responses by alloreactive T cells. In contrast, IFN-α did not induce IL-12 but, rather, augmented IL-10 production. IFN-α-primed matured CD11c+ DCs induced IL-10-producing regulatory T cells; however, this process was independent of the DC-derived IL-10. On the other hand, IFN-α by itself neither matured CD11c− DCs nor altered the polarization of responding T cells, although this cytokine was a potent survival factor for CD11c− DCs. Unlike IFN-α, IL-3 was a potent survival factor and induced the maturation of CD11c− DCs. The IL-3-primed CD11c− DCs activated T cells to produce IL-10, IFN-γ, and IL-4. Thus, CD11c+ and CD11c− DC subsets play distinct roles in the cytokine network, especially their responses to IFNs.