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First published online December 17, 2008
doi: 10.1242/10.1242/jcs.035089
Cell Science at a Glance |
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
* Author for correspondence (e-mail: paul.roche{at}nih.gov)
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Introduction |
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 Top Introduction Movement of newly synthesized...Sorting of MHC class...A model for the...Regulation of antigen loading...MHC class II trafficking...Re-entry of MHC-class-II-peptide...PerspectivesReferences |
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; van Niel et al., 2006). In this Cell Science at a Glance poster article we will describe the mechanisms that lead to MHC class II trafficking to intracellular sites of foreign-antigen degradation, MHC class II binding to antigenic fragments, and the movement of MHC-class-II–antigen complexes to the surface of the APC. It should be pointed out that the models presented here are based on our interpretation of the literature and, like all models, ours will have supporters and detractors. Nevertheless, the complex issues of MHC class II transport and antigen binding provide a cell-biological perspective to a `real world' biological issue that is crucially important for human health and welfare.
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Movement of newly synthesized MHC class II molecules into antigen-processing compartments |
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TopIntroductionMovement of newly synthesized...Sorting of MHC class...A model for the...Regulation of antigen loading...MHC class II trafficking...Re-entry of MHC-class-II-peptide...PerspectivesReferences |
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- and β-chains that are assembled in the endoplasmic reticulum (ER) together with a chaperone protein termed invariant chain (Ii) (Wolf and Ploegh, 1995). Ii serves to both stabilize the β heterodimer and inhibit inappropriate binding of antigen to the MHC class II peptide-binding groove. The newly formed β-Ii complex exits the ER, traffics through the Golgi complex and the trans-Golgi network (TGN) and is ultimately delivered to lysosome-like antigen-processing compartments. Although there is still some debate as to whether MHC class II traffics to these compartments directly from the TGN, we have proposed (and favor) a pathway that involves an intermediate step at the plasma membrane (PM) (Hiltbold and Roche, 2002): after arrival at the PM from the TGN, the β-Ii complex is efficiently sorted into the endocytic pathway by the recognition of two dileucine-based signals in the cytoplasmic tail of Ii by the clathrin adaptor AP-2, a scaffolding-protein complex that brings together components of the vesicle-formation machinery. The AP-2 complex sorts the β-Ii complex into clathrin-coated vesicles, which pinch off from the PM and fuse with endocytic compartments (Dugast et al., 2005; McCormick et al., 2005). Although Ii is not absolutely required for the localization of MHC class II molecules to endocytic structures, the efficiency with which MHC class II enters antigen-processing compartments is greatly enhanced by its association with Ii. |
Sorting of MHC class II molecules into intraluminal vesicles of multivesicular antigen-processing compartments |
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TopIntroductionMovement of newly synthesized...Sorting of MHC class...A model for the...Regulation of antigen loading...MHC class II trafficking...Re-entry of MHC-class-II-peptide...PerspectivesReferences |
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). Upon reaching the late endosomes, proteins that are intended for destruction are sorted onto intraluminal vesicles that are derived from the inward budding of the limiting membrane of the endosome, thereby giving rise to multivesicular antigen-processing compartments termed multivesicular bodies (MVBs). The endosomal sorting complex required for transport (ESCRT) protein machinery, either directly through the recognition of the small molecule ubiquitin or indirectly through ubiquitin-independent targeting, sorts molecules that are intended for destruction into subdomains of the MVB limiting membrane (Piper and Katzmann, 2007). These subdomains are enriched in tetraspanins and cholesterol, molecules that form microdomains that have been implicated in intraluminal vesicle biogenesis (Piper and Katzmann, 2007). Interestingly, several other lipids, including lysobisphosphatidic acid and ceramide, directly induce the inward budding of liposomes (Matsuo et al., 2004; Trajkovic et al., 2008), suggesting that the lipid microenvironment in late endosomes also plays a role in protein sorting and intraluminal-vesicle formation.
In the case of MHC class II, once in the endocytic pathway, β-Ii complexes are delivered to lysosome-like multivesicular antigen-processing compartments not for degradation, but for antigenic-peptide binding. Although it is clear that both immature (Ii-associated) and mature (peptide-loaded) MHC class II is found on intraluminal vesicles of these structures (Kleijmeer et al., 2001; Kleijmeer et al., 1997; Peters et al., 1995), the mechanism that regulates the movement of MHC class II to the intraluminal vesicles of MVBs has not been fully resolved. MHC class II is ubiquitylated in immature, but not mature, dendritic cells (DCs) (Shin et al., 2006; van Niel et al., 2006), and this modification is added solely to β complexes that are devoid of Ii (van Niel et al., 2006). These data suggest that β-Ii complexes sort onto the intraluminal vesicles of MVBs through an ubiquitin-independent pathway. However, there are conflicting reports regarding the relevance of ubiquitylation to the sorting of MHC-class-II-β–peptide complexes onto intraluminal vesicles of MVBs (Shin et al., 2006; van Niel et al., 2006), and further study will be required to unambiguously delineate the mechanisms that regulate the movement of MHC class II in MVBs.
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A model for the mechanism of antigen loading onto MHC class II molecules |
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TopIntroductionMovement of newly synthesized...Sorting of MHC class...A model for the...Regulation of antigen loading...MHC class II trafficking...Re-entry of MHC-class-II-peptide...PerspectivesReferences |
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), leaving behind a small fragment, termed CLIP (class-II-associated invariant chain peptide), that is bound to the MHC class II peptide-binding groove. Removal of CLIP is facilitated by the MHC-class-II-like chaperone protein HLA-DM via direct binding to the β-CLIP complex. HLA-DM then stabilizes the empty MHC class II molecule and presumably allows repeated binding and dissociation of peptides to MHC class II until primarily high-affinity antigenic peptides are bound to the peptide-binding groove (Busch et al., 2005). Thus, HLA-DM serves to edit the peptide repertoire of the APC. Interestingly, unlike MHC class II, HLA-DM is primarily retained on the limiting membrane of the MVB, and recent data suggest that an efficient interaction between MHC class II and HLA-DM requires their expression on disparate membranes (Zwart et al., 2005). |
Regulation of antigen loading onto MHC class II molecules |
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TopIntroductionMovement of newly synthesized...Sorting of MHC class...A model for the...Regulation of antigen loading...MHC class II trafficking...Re-entry of MHC-class-II-peptide...PerspectivesReferences |
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). Inhibition of HLA-DM activity leads to a concomitant increase in β-CLIP complexes in both the intracellular antigen-processing compartments and at the PM, and results in diminished immune responses. Recently, primary DCs were shown to also express HLA-DO (Hornell et al., 2006), suggesting that this form of regulation might be more ubiquitous than previously thought. In addition to HLA-DM inhibition, the regulated expression of the endosomal proteases cathepsin S and cathepsin L leads to reduced antigen presentation by inhibiting Ii degradation and/or antigenic-peptide formation (Hsing and Rudensky, 2005). Curiously, although it might be easiest to imagine that a free peptide simply diffuses into the empty MHC class II peptide-binding site, there is increasing evidence that partially unfolded proteins actually bind to this site, with the antigen fragments that reside outside of the peptide-binding groove being `chewed-back' by lysosomal proteases (Sercarz and Maverakis, 2003), further complicating our understanding of an already complicated process.
The lysosomal microenvironment has also been implicated in the regulation of antigen loading. In immature DCs, the elevated pH in lysosome-like organelles results in the inefficient degradation of endocytosed material into antigenic peptides (Trombetta et al., 2003). Upon DC maturation, the ATP-dependent vacuolar proton pump (V-ATPase) is activated, leading to acidification of these compartments, increased antigen proteolysis and efficient peptide loading onto MHC class II molecules (Trombetta et al., 2003). The absolute amount of proteinases is lower in professional APCs than in highly destructive cells such as macrophages (Delamarre et al., 2006; Delamarre et al., 2005), suggesting that APCs possess mechanisms that `control' proteolysis to limit the destruction of antigenic peptides.
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MHC class II trafficking to the plasma membrane |
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TopIntroductionMovement of newly synthesized...Sorting of MHC class...A model for the...Regulation of antigen loading...MHC class II trafficking...Re-entry of MHC-class-II-peptide...PerspectivesReferences |
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) and, although it has been proposed that this loss is due to the back-fusion of the peptide-loaded MHC-class-II-containing intraluminal vesicles with the MVB limiting membrane, their loss owing to degradation or release as exosomes has not been ruled out. Once MHC class II is redistributed to the limiting membrane of the MVB, it is moved into tubulovesicular structures that appear to fuse directly with the PM (Chow et al., 2002). As peptide-loaded MHC class II is abundant on the surface of immature DCs as well, it is likely that this mode of transport is simply enhanced upon DC maturation, allowing for more expression at the cell surface after activation.
Interestingly, MHC class II associates with lipid rafts, membrane microdomains that are rich in cholesterol and sphingolipids, in both the multivesicular antigen-processing compartment as well as at the PM (Poloso et al., 2004). Disruption of APC lipid-raft integrity leads to antigen-specific defects in T-cell activation that can be overcome by loading the APCs with large amounts of antigen (Anderson et al., 2000). This suggests that clustering of the MHC-class-II–peptide complexes in membrane microdomains serves to potentiate the activation of T cells. In addition to lipid rafts, a pool of MHC class II is also present in a membrane microdomain termed the tetraspan web (Vogt et al., 2002). Indeed, lipid rafts, MHC-class-II–peptide complexes and tetraspan-web proteins concentrate at the site of the immunological synapse that exists at the interface between APCs and T cells (Hiltbold et al., 2003; Vogt et al., 2002). These findings indicate that the lipid and/or membrane microenvironment in which MHC class II is trafficked plays a key role in determining the antigenicity of a given MHC-class-II–peptide complex.
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Re-entry of MHC-class-II–peptide complexes into the endocytic pathway from the plasma membrane |
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TopIntroductionMovement of newly synthesized...Sorting of MHC class...A model for the...Regulation of antigen loading...MHC class II trafficking...Re-entry of MHC-class-II-peptide...PerspectivesReferences |
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), and it has been proposed that ubiquitylation enhances MHC class II endocytosis (Shin et al., 2006; van Niel et al., 2006). Supporting this finding, overexpression of MARCH I leads to downregulation of MHC-class-II–peptide complexes at the surface (Matsuki et al., 2007). Unlike MHC-class-II–Ii complexes, the internalization of peptide-loaded MHC class II occurs independently of clathrin, AP-2 or the GTPase dynamin. Instead, these MHC-class-II–peptide complexes internalize and recycle in tubules containing Arf6 and Rab35, which are small GTPases that are thought to be involved in clathrin-independent protein sorting (Walseng et al., 2008). Upon DC maturation, expression of MARCH I is downregulated, inhibiting the ubiquitylation of MHC-class-II–peptide complexes (De Gassart et al., 2008). Internalization of MHC-class-II–peptide complexes in mature DCs is then reduced, thereby leading to retention of peptide-bound MHC class II at the surface. Thus, there is a balance struck between the surface transport and endocytosis of MHC-class-II–peptide complexes in DCs, with the result being relatively lower surface expression of MHC class II in immature DCs than in mature DCs. |
Perspectives |
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TopIntroductionMovement of newly synthesized...Sorting of MHC class...A model for the...Regulation of antigen loading...MHC class II trafficking...Re-entry of MHC-class-II-peptide...PerspectivesReferences |
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Footnotes |
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References |
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TopIntroductionMovement of newly synthesized...Sorting of MHC class...A model for the...Regulation of antigen loading...MHC class II trafficking...Re-entry of MHC-class-II-peptide...PerspectivesReferences |
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