IFN‐α‐conditioned dendritic cells are highly efficient in inducing cross‐priming CD8⁺ T cells against exogenous viral antigens

Abstract

Dendritic cells (DC) generated after a short-term exposure of monocytes to IFN-a and GM-CSF (IFN-DC) are highly effective in inducing cross-priming of CD8 + T cells against viral antigens. We have investigated the mechanisms responsible for the special attitude of these DC and compared their activity with that of reference DC. Antigen uptake and endosomal processing capabilities were similar for IFN-DC and IL-4-derived DC. Both DC types efficiently cross-presented soluble HCV NS3 protein to the specific CD8 + T cell clone, even though IFN-DC were superior in cross-presenting low amounts of viral antigens. Moreover, when DC were pulsed with inactivated HIV-1 and injected into hu-PBL-SCID mice, the generation of virus-specific CD8 + T cells was markedly higher in animals immunized with IFN-DC than in mice immunized with CD40L-matured IL-4-DC. Of interest, in experiments with purified CD8 + T cells, IFN-DC were superior with respect to CD40L-matured IL-4-DC in inducing in vitro cross-priming of HIV-specific CD8 + T cells. This property correlated with enhanced potential to express the specific subunits of the IL-23 and IL-27 cytokines. These results suggest that IFN-DC are directly licensed for an efficient CD8 + T cell priming by mechanisms likely involving enhanced antigen presentation and special attitude to produce IL-12 family cytokines.

NK Cell Activation in the Antitumor Response Induced by IFN-α Dendritic Cells Loaded with Apoptotic Cells from Follicular Lymphoma Patients

“…Accordingly, enhanced killing of K562 and lymphoma cells by NK effectors could be demonstrated upon stimulation of lymphocytes with tumor cellloaded IFN-DC. Although the cross-talk between NK cells and mature DC has been largely described (19,20), it should be pointed out that, in contrast to classical monocyte-derived DC, IFN-DC were shown not to need any additional factors to behave like mature DC (7,10) and spontaneously produce chemokines known to promote NK cell recruitment (21). Moreover, differentiation of monocytes into IFN-DC in the presence of NK cells was previously shown to favor a more mature DC phenotype (22).…”

“…In our experimental conditions, the absence of any detectable paracrine secretion of IL-12 by IFN-DC suggests that DC/NK cross-talk does not rely on this cytokine. We previously demonstrated that IFN-DC spontaneously produce an array of inflammatory cytokines, including TNF-a, IL-1b, IL-6, IL-23, and IL-27, promoting a Th1-type response, but also a Th17-type response (10,28). Nonetheless, it cannot be ruled out that other molecules or cytokines expressed by IFN-DC or distinct T cell subsets may contribute to NK cell activation and enhancement of lytic activity toward lymphoma cells.…”

“…IFN-DC and conventional IL-4-DC were obtained according to our previously described procedure (7,10). Positively selected CD14 + monocytes were isolated by immunomagnetic selection (MACS Cell Isolation Kit; Miltenyi Biotec) and plated at 2 3 10 6 cells/ml in CellGro DC medium (CellGenix), supplemented with 500 U/ml GM-CSF (Genzyme) and 250 U/ml IL-4 (R&D Systems) or 10,000 U/ml IFN-a2b (Intron A; Schering Plough) for 3 d. PBL were obtained from PBMC following CD14 + monocyte depletion, and NK cells were purified from PBL by positive immunomagnetic selection (MACS Cell Isolation Kit; Miltenyi Biotec).…”

“…We described a new class of highly active monocyte-derived dendritic cells generated in the presence of IFN-a and GM-CSF (IFN-DC) within three days, in the absence of maturation factors and without the need for extensive operations or manipulations (7). Although IFN-DC exhibit some features of mature DC, including the ability to promote the efficient cross-priming of CD8 + cells (7)(8)(9)(10)(11), they also retain the capacity to efficiently engulf proteins and apoptotic cells. In contrast to conventional DC (IL-4-DC), IFN-DC are fully able to preserve internalized proteins from early degradation and to route Ag to the MHC class I-processing pathway, allowing long-lasting Ag presentation (9,11).…”

Sorafenib and a novel immune therapy in lung metastasis from hepatocellular carcinoma following hepatectomy: A case report

“…This suggests that the CD141 + cDC subset may be involved in the recognition or subsequent procession of DRibbles by DCs (14). In the presence of GM-CSF and IFN-α, monocytes may differentiate into IFN-DCs in vitro, which may have a more potent function in terms of CD8 T-cell cross-priming compared with traditional interleukin (IL)-4-DCs generated from monocytes stimulated by GM-CSF and IL-4 (13,24). It was previously demonstrated that IFN-DCs may cross-present DRibbles and prime human memory antigen-specific CD8 and CD4 T cells more effectively compared with IL-4-DCs (data not shown).…”