Antigen cross-presentation: extending recent laboratory findings to therapeutic intervention

Abstract

SummaryThe initiation of adaptive immune responses requires antigen presentation to lymphocytes. In particular, dendritic cells (DCs) are equipped with specialized machinery that promote effective display of peptide/major histocompatibility complexes (MHC), rendering them the most potent stimulators of naive T lymphocytes. Antigen cross-presentation to CD8 + T cells is an important mechanism for the development of specific cytotoxic T lymphocyte (CTL) responses against tumours and viruses that do not infect antigenpresenting cells. Here, we review recent findings concerning antigen crosspresentation to CD8 + T lymphocytes. Specific subtypes of DCs in the mouse have been defined as being especially endowed for antigen cross-presentation, and a human homologue of these DCs has recently been described. DC vaccination strategies for the prevention and treatment of human diseases have been under investigation in recent years, but have not generally reached satisfying results. We here provide an overview of new findings in antigen crosspresentation research and how they can be used for development of the next generation of human DC vaccines.

Fcγ receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3+ dendritic cells

“…28 For immune complexes, the requirements for endosomal processing and proteasome-mediated peptide generation are not fully clear, particularly for human myeloid DCs. 3,29 We therefore assessed in human MoDCs the role of antigen processing in the endosomal pathway and by the proteasome. We assessed cross-presentation of HCMV pp65 antigen to pp65-specific CD8 ϩ T-cell clones, as reported, 12,30 but in our case administered pp65 antigen as IgG-pp65 immune complexes to facilitate Fc␥R-mediated uptake.…”

“…3 We therefore first established our Fc␥R antigen targeting work in MoDCs, before moving into primary BDCA-3 ϩ DCs. We proposed that Fc␥R antigen targeting may potentiate DC vaccination-induced CD8 ϩ T-cell responses as in mice, [15][16][17] and therefore assessed Fc␥R expression on MoDCs, cultured in the presence of GM-CSF and IL-4 for 5 days.…”

“…14 Antigen targeting to specific receptors, including Fcgammareceptors (Fc␥R) directs antigen presentation toward the class I MHC or the class II MHC presentation pathway. 3,[15][16][17] Here, we addressed the possible role of Fc␥R-mediated antigen targeting as a mechanism within human BDCA-3 ϩ DCs. Fc␥R-mediated antigen targeting in BDCA-3 ϩ DCs, as we show, is particularly effective at potentiating antigen cross-presentation ability in these DCs, a process that is fully blocked when Fc␥R function is absent.…”

“…[1][2][3] Strategies that increase early antiviral adaptive immune responses after transplantation are therefore under exploration, which could ultimately help to establish full clearance of, and long-term immunologic memory against viruses. The induction of adaptive immune protection against, for example HCMV, requires the display of antigen by professional antigen presenting cells (APCs) to lymphocytes.…”

Molecular Mechanisms of TLR2-Mediated Antigen Cross-Presentation in Dendritic Cells

“…Exogenous Ags are cross-presented by MHC class I molecules through two pathways: 1) the TAP-dependent pathway (or the cytosolic pathway), in which Ags are digested by the proteasome and transported into either the endoplasmic reticulum (ER) (1) or the early endosome (2, 3) for loading onto MHC class I molecules; and 2) the TAP-independent pathway (or the vacuolar pathway), in which Ags are digested in the endolysosome and directly loaded onto MHC class I molecules (4,5). The TAPdependent pathway is associated with proteasomal degradation of cytosolic Ags.…”