Intracellular recycling and cross-presentation by MHC class I molecules.
Cross-presentation of internalized antigens by dendritic cells requires efficient delivery of Major Histocompatibility Complex (MHC) class I molecules to peptide-loading compartments. Strong evidence suggests that such loading can occur outside of the endoplasmic reticulum; however, the trafficking pathways and sources of class I molecules involved are poorly understood. Examination of non-professional, non-phagocytic cells has revealed a clathrin-independent, Arf6-dependent recycling pathway likely traveled by internalized optimally loaded (closed) class I molecules. Some closed and all open MHC class I molecules travel to late endosomes to be degraded but might also partly be re-loaded with peptides and recycled. Studies of viral interference revealed pathways in which class I molecules are directed to degradation in lysosomes upon ubiquitination at the surface, or upon AP-1 and HIV-nef-dependent misrouting from the Golgi network to lysosomes. While many observations made in non-professional cells remain to be re-examined in dendritic cells, available evidence suggests that both recycling and neo-synthesized class I molecules can be loaded with cross-presented peptides. Recycling molecules can be recruited to phagosomes triggered by innate signals such as TLR4 ligands, and may therefore specialize in loading with phagocytosed antigens. In contrast, AP-1-dependent accumulation at, or trafficking through, a Golgi compartment of newly synthesized molecules appears to be important for cross-presentation of soluble proteins and possibly of long peptides that are processed in the so-called vacuolar pathway. However, significant cell biological work will be required to confirm this or any other model and to integrate knowledge on MHC class I biochemistry and trafficking in models of CD8(+) T-cell priming by dendritic cells.
Institut National de la Santé et de la Recherche Médicale, Unité 1151, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Centre National de la Recherche Scientifique, Unité 8253, Paris, France.
Peter
P
van Endert
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology*; D006056:Golgi Apparatus / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space; D008213:Lymphocyte Activation; D008247:Lysosomes / Q000378:metabolism*; D021381:Protein Transport; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
MHC class I; cross-presentation; endosome