Abstract
BackgroundCross-presentation by dendritic cells (DCs) is a crucial prerequisite for effective priming of cytotoxic T-cell responses against bacterial, viral and tumor antigens; however, this antigen presentation pathway remains poorly defined.Methodology/Principal FindingsIn order to develop a comprehensive understanding of this process, we tested the hypothesis that the internalization of MHC class I molecules (MHC-I) from the cell surface is directly involved in cross-presentation pathway and the loading of antigenic peptides. Here we provide the first examination of the internalization of MHC-I in DCs and we demonstrate that the cytoplasmic domain of MHC-I appears to act as an addressin domain to route MHC-I to both endosomal and lysosomal compartments of DCs, where it is demonstrated that loading of peptides derived from exogenously-derived proteins occurs. Furthermore, by chasing MHC-I from the cell surface of normal and transgenic DCs expressing mutant forms of MHC-I, we observe that a tyrosine-based endocytic trafficking motif is required for the constitutive internalization of MHC-I molecules from the cell surface into early endosomes and subsequently deep into lysosomal peptide-loading compartments. Finally, our data support the concept that multiple pathways of peptide loading of cross-presented antigens may exist depending on the chemical nature and size of the antigen requiring processing.Conclusions/SignificanceWe conclude that DCs have ‘hijacked’ and adapted a common vacuolar/endocytic intracellular trafficking pathway to facilitate MHC I access to the endosomal and lysosomal compartments where antigen processing and loading and antigen cross-presentation takes place.
Highlights
In order to generate appropriate CD8+ T cell-mediated immune responses to viral, bacterial, self, or tumor-associated protein antigens, professional antigen-presenting cells must acquire these antigens from the extracellular milieu, process them into antigenic peptides, load them onto MHC class I (MHCI) molecules, and present them at the cell surface [1,2,3,4]
Constitutive internalization of MHC-I in dendritic cells is differentially affected by cytoplasmic tail mutations To elucidate the role of distinct cytoplasmic domain motifs in MHC-I molecular trafficking and function in vivo, we generated transgenic mice, described previously [21], expressing either wild type H-2Kb (KbWT), Kb containing a point mutation of the highly conserved exon 6-encoded tyrosine (DY), or Kb containing a deletion of 13 amino acids encoded by exon 7, including at least one highly conserved serine phosphorylation site (D7, Figure 1A)
Cross-presentation by dendritic cells (DCs) is a crucial prerequisite for effective priming of cytotoxic T-cell responses against bacterial, viral, and tumor antigens in vivo, several mechanistic aspects of these pathways remain poorly defined
Summary
In order to generate appropriate CD8+ T cell-mediated immune responses to viral, bacterial, self, or tumor-associated protein antigens, professional antigen-presenting cells (pAPCs) must acquire these antigens from the extracellular milieu, process them into antigenic peptides, load them onto MHC class I (MHCI) molecules, and present them at the cell surface [1,2,3,4]. This process of ‘‘cross-presentation’’ is known to occur most efficiently in dendritic cells (DCs), but several mechanistic details remain unclear. Cross-presentation by dendritic cells (DCs) is a crucial prerequisite for effective priming of cytotoxic T-cell responses against bacterial, viral and tumor antigens; this antigen presentation pathway remains poorly defined
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