Chapter One - Cross-Presentation in Mouse and Human Dendritic Cells
Introduction
Two main pathways have been described for antigen presentation: the presentation on major histocompatibility complex (MHC) class I or class II molecules. All nucleated cells express MHC class I molecules and can present MHC I–peptide complexes to CD8 T cells. These peptides are derived from endogenous proteins—or viral proteins produced in the infected cell—that are degraded by the proteasome in the cytosol. The resulting peptides are then trimmed by aminopeptidases and transported into the endoplasmic reticulum (ER) by TAP transporters before loading onto newly formed MHC class I molecules. By contrast, only a restricted set of cell populations express MHC class II molecules and can present MHC II–peptide complexes to CD4 T cells. These peptides are mainly derived from exogenous proteins that are degraded by proteases in endocytic compartments and then loaded onto MHC class II molecules in endosomes and lysosomes. An additional antigen presentation pathway has been described, allowing the presentation of exogenous protein-derived peptides on MHC class I molecules: the cross-presentation pathway. This pathway is even more restricted than the two others, as only dendritic cells (DCs) cross-present antigens efficiently, especially in vivo.
DCs are professional antigen-presenting cells equipped with the machinery to capture and process antigens, to present these antigens to T lymphocytes and to provide additional signals that orient immune responses. Most of these signals are dictated by the recognition of pathogen-derived products through specific receptors, among which the toll-like receptors (TLR) are the best studied. In vivo ablation of DCs abolished cross-presentation of pathogen-associated antigens (Jung et al., 2002), showing that DCs are the main cross-presenting cells in mice. DCs represent a complex array of subpopulations found in secondary lymphoid organs and in most peripheral tissues and nonlymphoid organs. Because DCs are rare and difficult to isolate, in vitro culture models of DCs have been predominantly used to analyze the cell biology of cross-presentation, mainly bone-marrow-derived DCs (BMDCs) for mouse (Inaba et al., 1992) and monocyte-derived DCs for human (Sallusto & Lanzavecchia, 1994). However, the equivalence of these culture-generated DCs to in vivo DC subpopulations remains unclear.
In this chapter, we will describe the current view of the molecular mechanisms of cross-presentation and of the role of the different DC subsets in this process, both in mouse and human. Finally, we will summarize recent advances in our understanding of the function of cross-presentation in pathological situations, namely viral infections, autoimmunity, and cancer.
Section snippets
Cytosolic Versus Vacuolar Pathway
Two pathways have been proposed for cross-presentation, depending on where antigen processing occurs (Fig. 1). In the cytosolic pathway, internalized antigens are transferred from the lumen of endocytic compartments to the cytosol where they are degraded by the proteasome. Degradation products are then transported by TAP, either into the ER or into the lumen of endosomes or phagosomes, for loading onto MHC class I molecules. In the vacuolar pathway, internalized antigens are degraded within
Overview of Mouse and Human DC Subsets
Steady-state DCs can be divided into pDCs and “classical” DCs (cDCs). cDCs are composed of two main groups: resident and migratory DCs. Resident DCs populate secondary lymphoid organs and remain there during their entire life cycle. Migratory DCs are present in peripheral tissues and nonlymphoid organs and can migrate through the lymph to the closest draining lymph nodes. Finally, resident and migratory DCs can be further separated into several subsets that are best described according to their
Cross-Presentation During Viral Infections
The importance of cross-presentation during viral infections is likely dependent on the virus type, tropism, and infection route. Viral antigens can theoretically be presented by DCs on MHC class I molecules either via direct presentation in infected DCs or via cross-presentation after acquisition of viral antigens from neighboring infected cells. In vaccinia virus infection, direct presentation by infected DCs was shown to play a major part in CD8 T cell priming. Using recombinant vaccinia
Conclusion and Perspectives
Cross-presentation is now considered to represent a major pathway for CD8 T cell responses in many physiological and pathological experimental models. However, this conclusion still relies on indirect evidence. Indeed, specific limiting factors of the cross-presentation pathway, which would not be involved in the endogenous MHC class I nor in the exogenous MHC class II presentation pathways, remain unknown. Consequently, it is still impossible to evaluate precisely the contribution of
Acknowledgments
Our work is supported by INSERM, Institut Curie, European Research Council (2008-AdG n°233062 PhagoDC) and Ligue contre le Cancer. The authors have no competing financial interests.
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