The ongoing saga of the mechanism(s) of MHC class I-restricted cross-presentation

Abstract

Cross-presentation is an MHC-I antigen processing pathway that results in the presentation of peptides from exogenous viral, bacterial, parasitic, and tumor antigens and ultimately leads to priming of naïve CD8+ T cells. This process involves several cellular compartments and multiple components. Successful generation of MHC-I-peptide complexes requires that these components act together in a coordinated fashion. We discuss recent findings on the source of MHC-I, the role of the TAP transporter, the importance of intracellular trafficking events, mechanisms of antigens access the cytosol, and how innate immune signals can affect presentation, with an emphasis on how these pathways compare to conventional antigen presentation and how they correlate with existing data.

Proteasomal degradation within endocytic organelles mediates antigen cross‐presentation

“…Initiation of a CTL response requires priming of naïve CD8-positive T lymphocytes by professional antigen presenting cells, normally dendritic cells (DCs), by a mechanism called cross-priming or crosspresentation (Grotzke et al, 2017). Initiation of a CTL response requires priming of naïve CD8-positive T lymphocytes by professional antigen presenting cells, normally dendritic cells (DCs), by a mechanism called cross-priming or crosspresentation (Grotzke et al, 2017).…”

“…Cytotoxic T lymphocytes (CTL) that eliminate virus-infected cells or tumors do so by recognizing MHC-I molecules associated with short peptides derived from viral or tumor-specific protein antigens. Initiation of a CTL response requires priming of naïve CD8-positive T lymphocytes by professional antigen presenting cells, normally dendritic cells (DCs), by a mechanism called cross-priming or crosspresentation (Grotzke et al, 2017). This involves endocytosis of antigenic proteins or phagocytosis of virally infected cells or tumor cells followed by antigen proteolysis and binding of resulting peptides by MHC-I molecules.…”

“…An alternative mechanism, commonly called the vacuolar pathway, postulates that the peptides are generated by endocytic or phagosomal proteases before binding to recycling MHC-I molecules (Song & Harding, 1996). However, this mechanism implies that the production of identical MHC-I-binding peptides by vacuolar enzymes in cross-presenting DCs and cytosolic proteasomes in the target cell is a matter of chance (Grotzke et al, 2017). Here, we present an alternative to this model for the vacuolar pathway.…”

Endocytosed soluble cowpox virus protein CPXV012 inhibits antigen cross‐presentation in human monocyte‐derived dendritic cells

“…Upon exogenous antigen uptake by DCs, two main pathways are involved in MHC I antigen cross‐presentation (reviewed in ). A TAP‐independent vacuolar pathway requires lysosomal acidification and subsequent antigen degradation by endolysosomal proteases.…”

“…4 In addition, proteins typically involved in endogenous MHC I antigen presentation may also play a role in cross-presentation, including the proteasome and TAP. [4][5][6][7][8][9] Upon exogenous antigen uptake by DCs, two main pathways are involved in MHC I antigen crosspresentation (reviewed in [10][11][12][13][14]. A TAP-independent vacuolar pathway requires lysosomal acidification and subsequent antigen degradation by endolysosomal proteases.…”