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

Abstract

The 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 antigen-presenting cells. Here, we review recent findings concerning antigen cross-presentation 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 cross-presentation research and how they can be used for development of the next generation of human DC vaccines.

Fig. 1

Proposed pathways of antigen cross-presentation. Yellow area (left side) relates to mechanisms described only in mice so far, whereas the gradient towards the red area (right side) depicts the transient increase in knowledge of antigen cross-presentation mechanisms in human cells. By receptor-mediated endocytosis, the antigen (red rod shape) is engulfed into a phagosome and subsequently processed in a cytosolic proteasome- (a,b,c) or endosomal protease-dependent (d) manner. For proteasome-mediated degradation the antigen is transported across the endosomal membrane into the cytosol by Sec61, accessed by the proteasome via endoplasmic reticulum (ER)–endosome fusion (c) or a delivery vesicle derived from the ER (a,b). After processing by the proteasome, possibly assisted by cytosolic peptidases, peptides either re-enter the endosomal compartment via transporter associated with antigen processing (TAP) where loading on class I major histocompatibility complex (MHC) may occur (a), or the canonical class I MHC presentation pathway in the ER (b,c). After proteolytic processing by endosomal pathway-resident proteases, peptides are loaded onto class I MHC molecules by replacing either exogenous peptide (recycling) or endogenous peptide (classical) loaded on class I MHC complexes (d). : antigen; : exogenous peptide; : endogenous peptide; : Sec61; : TAP; : MHC class I molecules; : proteasome; : proteases.