Cross-presentation by dendritic cells

• Published in: Nature reviews. Immunology Vol. 12; no. 8; pp. 557 - 569
• Main Authors: Joffre, Olivier P., Segura, Elodie, Savina, Ariel, Amigorena, Sebastian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2012; Nature Publishing Group
• Subjects: 20; 21; 631/250/2152/569; 631/250/251; Adaptations; Animals; Antigen presentation; Antigen processing; Antigens; Autoantigens; Biomedical and Life Sciences; Biomedicine; CD8 antigen; CD8 lymphocytes; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cross-Priming - immunology; Cytosol; Cytotoxicity; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - immunology; Endoplasmic reticulum; Endosomes; Epithelial cells; Histocompatibility Antigens Class I - immunology; Humans; Immune Tolerance - immunology; Immunity; Immunological tolerance; Immunology; Immunotherapy; Inflammation; Lymphocytes T; Major histocompatibility complex; Mice; Peptides; Phagocytes; Phagosomes; Properties; Proteasomes; Proteins; Proteolysis; review-article; Reviews; Specialization; Subpopulations; Thymus; France; Paris France
• ISSN: 1474-1733; 1474-1741
• DOI: 10.1038/nri3254

Key Points
Two main pathways have been described for cross-presentation: the cytosolic pathway, in which antigen processing occurs in the cytosol, and the vacuolar pathway, in which antigen processing occurs within endocytic compartments. For both pathways, the origin and the site of loading of MHC class I molecules are still incompletely understood.
Limited proteolysis in the endocytic compartments of dendritic cells (DCs) favours cross-presentation by preventing the destruction of internalized antigens.
In the cytosolic pathway, exogenous antigens are translocated from endosomal compartments into the cytosol for degradation by the proteasome. The molecular machinery involved remains poorly characterized, but several lines of evidence suggest a role for endoplasmic reticulum proteins that could be delivered to endosomes and phagosomes through a specific pathway in cross-presenting DCs.
There are several subpopulations of mouse DCs, of which only some can efficiently cross-present antigens, probably owing to specific features of their endocytic compartments that favour cross-presentation through the cytosolic pathway. Whether some of the human DC subsets are also specialized at cross-presentation remains unclear.
During infections, cross-presentation is essential for the initiation of cytotoxic CD8
+
T cell responses when DCs are not directly infected. The DC subsets involved differ depending on the site of infection and the inflammatory environment.
Cross-presentation of thymic epithelial cell-associated antigens by thymic DCs is involved in the deletion of autoreactive CD8
+
T cells. In the periphery, cross-presentation of self antigens by DCs is also important for the maintenance of tolerance.
The manipulation of cross-presentation and
in vivo
targeting of cross-presenting DCs for the delivery of vaccines have proved promising strategies in mice, but a better understanding of human DC subsets is needed for translation to the clinic.
This Review integrates recent evidence regarding the intracellular trafficking pathways involved in cross-presentation into our understanding of the role of cross-presentation in immunity and tolerance.
The presentation of exogenous antigens on MHC class I molecules, known as cross-presentation, is essential for the initiation of CD8
+
T cell responses.
In vivo
, cross-presentation is mainly carried out by specific dendritic cell (DC) subsets through an adaptation of their endocytic and phagocytic pathways. Here, we summarize recent advances in our understanding of the intracellular mechanisms of cross-presentation and discuss its role in immunity and tolerance in the context of specialization between DC subsets. Finally, we review current strategies to use cross-presentation for immunotherapy.