Abstract
Antigen-presenting cells survey their environment and present captured antigens bound to major histocompatibility complex (MHC) molecules. Formation of MHC-antigen complexes occurs in specialized compartments where multiple protein trafficking routes, still incompletely understood, converge. Autophagy is a route that enables the presentation of cytosolic antigen by MHC class II molecules. Some reports also implicate autophagy in the presentation of extracellular, endocytosed antigen by MHC class I molecules, a pathway termed “cross-presentation.” The role of autophagy in cross-presentation is controversial. This may be due to studies using different types of antigen presenting cells for which the use of autophagy is not well defined. Here we report that active use of autophagy is evident only in DC subtypes specialized in cross-presentation. However, the contribution of autophagy to cross-presentation varied depending on the form of antigen: it was negligible in the case of cell-associated antigen or antigen delivered via receptor-mediated endocytosis, but more prominent when the antigen was a soluble protein. These findings highlight the differential use of autophagy and its machinery by primary cells equipped with specific immune function, and prompt careful reassessment of the participation of this endocytic pathway in antigen cross-presentation.
Highlights
Understanding of macroautophagy has evolved from recognizing its function in the survival of starved cells to the realization that autophagy is a pathway that can be co-opted for specialized cell functions.[1]
We tested the hypothesis that if autophagy contributes to cross-presentation, it should be more prominent in mouse primary dendritic cells (DC) specialized in this function
Mouse CD8C DC are the dominant cross-presenters in vivo,[16,17] so we compared their use of autophagy to that in CD8¡ DC, that are not capable of crosspresentation
Summary
Understanding of macroautophagy (referred as autophagy) has evolved from recognizing its function in the survival of starved cells to the realization that autophagy is a pathway that can be co-opted for specialized cell functions.[1]. Autophagy enables cells to expand the repertoire of antigens presented via this pathway by delivering cytosolic material to endo-lysosomal compartments, where it can be used as a source of MHC II peptide ligands.[4,5,6] Another route for presentation of endocytosed antigens, in which autophagy has been suggested to participate, is cross-presentation. Most studies to date have examined autophagy in monocyte-derived DC generated in culture from bone marrow precursors This is a model that does not resemble the complex functional specializations exhibited by their natural counterparts produced in vivo.[13] cross-presentation by monocyte-derived DC does not involve the canonical endosome-to-cytosol route required for cross-presentation of viral and tumor antigens in vivo.[14] the contribution of autophagy to specialized DC biology remains largely unknown. We have investigated the use of autophagy by cross-presenting and non-cross-presenting primary DC contained in mouse and human lymphoid organs, and assessed the role of this endosomal trafficking pathway in cross-presentation
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