Immature Dendritic Cells Phagocytose Apoptotic Cells via αvβ5 and CD36, and Cross-present Antigens to Cytotoxic T Lymphocytes

Abstract

SummaryDendritic cells, but not macrophages, efficiently phagocytose apoptotic cells and cross-present viral, tumor, and self-antigens to CD8 ϩ T cells. This in vitro pathway corresponds to the in vivo phenomena of cross-priming and cross-tolerance. Here, we demonstrate that phagocytosis of apoptotic cells is restricted to the immature stage of dendritic cell (DC) development, and that this process is accompanied by the expression of a unique profile of receptors, in particular the ␣ v ␤ 5 integrin and CD36. Upon maturation, these receptors and, in turn, the phagocytic capacity of DCs, are downmodulated. Macrophages engulf apoptotic cells more efficiently than DCs, and although they express many receptors that mediate this uptake, they lack the ␣ v ␤ 5 integrin. Furthermore, in contrast to DCs, macrophages fail to cross-present antigenic material contained within the engulfed apoptotic cells. Thus, DCs use unique pathways for the phagocytosis, processing, and presentation of antigen derived from apoptotic cells on class I major histocompatibility complex. We suggest that the ␣ v ␤ 5 integrin plays a critical role in the trafficking of exogenous antigen by immature DCs in this cross-priming pathway.

Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

“…49 As to the maturation stage of DCs, we used relatively immature DCs that were derived from BM and cultured in the presence of GM-CSF and IL-4 for 7 days, since immature DCs are believed to be efficient in taking up foreign antigens by phagocytosis. 23,41,50 Based on in vitro and in vivo data in the present study, we hypothesize that immature DCs may be attracted to the tumor site, where they may take up antigens, and after undergoing maturation and changes in chemokine receptors, they may migrate to the CLNs.…”

“…glioma models and have demonstrated preclinical efficacy. 19,20 Effective presentation of tumor antigens by DCs is considered to be an essential step for effective induction of antitumor T-cell responses, and both necrotic 21 and apoptotic tumor cells [22][23][24] are known to be good antigen sources for DCs. We therefore hypothesized that transfection of glioma cells with IFN-a and provision of DCs would prove even more effective in driving antitumor immunity than IFN gene transfer alone, since this strategy would facilitate the apoptosis of glioma cells and prompt crosspresentation of glioma antigens by DCs to specific T cells.…”

Transduction of dendritic cells with recombinant adenovirus encoding HCA661 activates autologous cytotoxic T lymphocytes to target hepatoma cells

“…In humans, adenoviral vectors expressing immunostimulatory cytokines or tumour antigens have recently been used to elicit antitumour immunity in gene therapy (MolnarKimber et al, 1998;Schuler et al, 1998). However, mature DCs are less susceptible to transfection than immature DCs (Zhong et al, 1999), due to reduced expression of a v b 5 integrin (Albert et al, 1998) that mediates the uptake of adenoviruses (Wickham et al, 1993). In our study, we transfected immature DCs with recombinant adenovirus and then induced the DCs to mature by using the maturation agent.…”

Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1

“…37 The elimination of apoptotic cells and cell bodies by phagocytes represents an evolutionarily conserved means to prevent exposure of surrounding tissue to potentially cytotoxic, immunogenic or inflammatory cellular content. 38,39 Resolution of inflammation depends not only on the removal of apoptotic cells but also on active suppression of inflammatory mediator production. Aberrations in either mechanism are associated with chronic inflammatory conditions and autoimmune disorders.…”