The latter contain abundant MHCII-labeled internal membrane sheets, and high-resolution three-dimensional 3D analysis of these compartments suggests that they represent lysosomal compartments with MHCII trapped on their inner membranes, possibly in the process of being degraded Murk et al. Reduction in ILV targeting leads to rerouting of pMHCII to the cell surface, possibly by default see above , therewith elevating expression levels at the plasma membrane.
One mechanism could involve deubiquitination, although MHCII-specific deubiquitinating enzyme s have not yet been identified. Yet other undiscovered regulatory mechanisms may provide additional modes to regulate ubiquitination of MHCII. The central role of MHC ubiquitination in antigen presentation is also illustrated by reports on how certain pathogens can suppress immunity by targeting this system Ishido et al.
In this regard, it was recently shown that sorting of MHCII is highly dependent on the length of the conjugated ubiquitin chain Ma et al. The biological relevance of ubiquitination-driven MHCII traffic has also been investigated in vivo and has generated some dispute.
Others concluded that ubiquitin-dependent control of MHCII localization is dispensable for antigen presentation and antibody production McGehee et al. It has been debated whether peptide loading occurs preferentially at the endosomal-delimiting membrane or at ILVs. In this case, a pathway should exist for pMHCII to travel back from ILVs to the endosomal-delimiting membrane from where it could then reach the plasma membrane. More recently, however, it was shown that such membrane tubules can be generated as a consequence of homotypic endosome fusion Skjeldal et al.
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Several lines of more convincing evidence support the idea that MHCII peptide loading occurs at the endosomal-delimiting membrane, in contrast to ILVs. Thus, Ii is already processed into CLIP and ready for peptide loading at the endosomal-delimiting membrane. MHCII peptide loading and ubiquitinaton are not necessarily mechanistically linked, and the sequence of events could merely be dictated by differences in kinetics.
In this line of thought, and consistent with our data ten Broeke et al. This poses a conceptual problem that has not yet been fully resolved. How does the immune system prevent the activation of self-reactive T cells by activated DCs that in addition to foreign peptides also display self peptides in the context of MHCII? In response to DC activation by pathogens, the selectivity of loading microbial-derived antigens over self peptides is achieved through transient up-regulation followed by shutoff of MHCII synthesis in combination with a change in the sorting behavior of newly synthesized MHCII at the endocytic tract Villadangos et al ; ten Broeke et al.
Another way to increase selectivity in antigen presentation is the formation of pMHCII microdomains that are preformed within phagosomes and maintained upon arrival at the DC plasma membrane Bosch et al. Further specificity may be achieved through autonomous control by phagosomes in contributing pMHCII for presentation, meaning that antigens are preferentially presented by MHCII when originating from antigen-carrying particles that also stimulate DC-activating receptors from within that same compartment Blander and Medzhitov ; Hoffmann et al. This idea is supported by the observations that TLR2 Underhill et al.
TLR delivery to phagosomes requires the clathrin adaptor AP-3, and local signaling facilitates pMHCII recruitment from phagosomes for presentation at the plasma membrane Mantegazza et al. Clearly, pMHCII can also be recruited to the plasma membrane from endocytic compartments other than phagosomes, but recruitment from PAMP-carrying phagosomes may prevail.
To achieve immune evasion, pathogens like Salmonella Lapaque et al. Phagosomes that carry less sophisticated pathogens might stabilize MHCII molecules through local interference with ubiquitination. Transfer of pMHCII from pathogen-loaded phagosomes to the plasma membrane can occur unidirectionally, for example, toward immunological synapse between DC and T cells Boes et al. Ubiquitination of MHCII is regulated, possibly differentially depending on the subcellular location, by largely unknown mechanisms.
The potential role of phagosome autonomy herein also needs to be explored. Such knowledge may be instrumental to design more efficient vaccination strategies, for example, through physical coupling of vaccine antigens to immune adjuvants. Disclosure of mechanisms by which some bacteria and viruses avoid immune surveillance by enhancing MHCII traffic to lysosomes may help development of novel medicines toward such pathogens. Finally, whether failure of proper regulation of MHCII ubiquitination can contribute to the development of autoimmune diseases also needs to be investigated.
We thank Guillaume van Niel, Marca Wauben, Lisette Nijland, and Birol Cabukusta, as well as other laboratory members and collaborators for their contributions to our work and stimulating discussions. We apologize to all colleagues whose work could not be cited because of space limitations. We thank Utrecht University for support and funding. Additional Perspectives on Endocytosis available at www. Previous Section Next Section.
Figure 1. Figure 2. Figure 3. Previous Section. Intracellular mechanisms of antigen cross presentation in dendritic cells. Curr Opin Immunol 22 : — Invariant chain cleavage and peptide loading in major histocompatibility complex class II vesicles. J Exp Med : — Nat Immunol 12 : 54 — CrossRef Medline Google Scholar. Invariant chain can function as a chaperone protein for class II major histocompatibility complex molecules. Proc Natl Acad Sci 89 : — Phosphorylation regulates the delivery of MHC class II invariant chain complexes to antigen processing compartments.
J Immunol : — Nat Immunol 1 : — Transport properties of free and MHC class ll-associated oligomers containing different isoforms of human invariant chain. Int Immunol 6 : — Ubiquitination of CD86 is a key mechanism in regulating antigen presentation by dendritic cells. Downregulation of major histocompatibility complex class I by human ubiquitin ligases related to viral immune evasion proteins. J Virol 78 : — The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain.
Medline Google Scholar. Tetraspanins as regulators of protein trafficking. Traffic 8 : 89 — Major histocompatibility complex class II-associated p41 invariant chain fragment is a strong inhibitor of lysosomal cathepsin L. Mapping functional regions in the lumenal domain of the class II-associated invariant chain. Toll-dependent selection of microbial antigens for presentation by dendritic cells.
Nature : — Pathways of antigen processing. Annu Rev Immunol 31 : — In vivo control of endosomal architecture by class II-associated invariant chain and cathepsin S. Eur J Immunol 35 : — Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 72 : — MHC class II—peptide complexes arrive at the plasma membrane in cholesterol-rich microclusters. J Biol Chem : — J Cell Sci : — Invariant chain protects class II histocompatibility antigens from binding intact polypeptides in the endoplasmic reticulum.
EMBO J 15 : — MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic 10 : — Extensive trafficking of MHC class II-invariant chain complexes in the endocytic pathway and appearance of peptide-loaded class II in multiple compartments. Immunity 2 : 73 — Biochemical characterization of an invariant polypeptide associated with Ia antigens in human and mouse.
Loading of MHC I with peptides is a two-step iterative process
Mol Immunol 20 : 21 — Regulation of major histocompatibility complex class II genes. Curr Opin Immunol 23 : 81 — Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Balancing between immunity and tolerance: An interplay between dendritic cells, regulatory T cells, and effector T cells. J Leukoc Biol 82 : — Lysosomal cysteine and aspartic proteases are heterogeneously expressed and act redundantly to initiate human invariant chain degradation.
Mechanisms of MHC class I-restricted antigen processing and cross-presentation. Immunol Rev : — Autophagy and adaptive immunity. Immunology : 9 — Proc Natl Acad Sci : — Cell 82 : — Science : — Right place, right time, right peptide: DO keeps DM focused. J Cell Biol : — The invariant chain is required for intracellular transport and function of major histocompatibility complex class II molecules. The protease inhibitor Cystatin C is differentially expressed among dendritic cell populations, but does not control antigen presentation.
Association of distinct tetraspanins with MHC class II molecules at different subcellular locations in human immature dendritic cells. Int Immunol 13 : — Molecular assemblies and membrane domains in multivesicular endosome dynamics. Exp Cell Res : — The segment of invariant chain that is critical for association with major histocompatibility complex class II molecules contains the sequence of a peptide eluted from class II polypeptides.
Proc Natl Acad Sci 90 : — Lysosomal trafficking, antigen presentation, and microbial killing are controlled by the Arf-like GTPase Arl8b. Immunity 35 : — Exon 6 is essential for invariant chain trimerization and induction of large endosomal structures. Peptide binding inhibits protein aggregation of invariant-chain free class II dimers and promotes surface expression of occupied molecules. Immunol Today 19 : — Early endosomes and a late endocytic compartment generate different peptide—class II MHC complexes via distinct processing mechanisms. Empty class II major histocompatibility complex created by peptide photolysis establishes the role of DM in peptide association.
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Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol 20 : — Dev Cell 21 : 77 — Cold Spring Harb Perpsect Biol 5 : a CrossRef Google Scholar. Biochim Biophys Acta : — Autonomous phagosomal degradation and antigen presentation in dendritic cells. The leucine-based sorting motifs in the cytoplasmic domain of the invariant chain are recognized by the clathrin adaptors AP1 and AP2 and their medium chains. Molecules, mechanisms, and cellular roles of clathrin-independent endocytosis.
Curr Opin Cell Biol 22 : — Crit Rev Biochem Mol Biol 45 : — The Rab11a GTPase controls Toll-like receptor 4—induced activation of interferon regulatory factor-3 on phagosomes. Immunity 33 : — Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. E3 ubiquitin ligases for MHC molecules. The MHC-II molecule cleft is made up of a noncovalent association between the a1 and b1 domains that bind the peptide through multiple van der Waals forces and hydrogen bonds.
The a1 and b1 domains are shown lying on a sheet of eight antiparallel b strands. The folding of the a1 and b1 domains creates a long cleft or groove that is the site at which peptide antigens bind to the MHC-II molecule and are presented to the CD4 lymphocyte. Figure 6. Endogenous proteins e. After trimming by cytosolic proteases 3 , the peptides enter the endoplasmic reticulum via the TAP 1 and TAP 2 transporters 4. Binding immunoglobulin protein BiP and endoplasmic reticulum protein 57 ERP57 , during which the b2 microglobulin is added to the alpha chain, complete the synthesis of the complete MHC-I molecule right inset in panel A.
The complex is held together by tapasin TPN , which facilitates transfer of the peptide to the antigen-binding cleft 5. The peptide-loaded MHC-I complex is then transferred to the Golgi 6 and then transported to the surface of the cell 7. Exogenous proteins are taken up 1 and processed in the early endosomal compartment 2 and cleaved into peptides by cathepsins and other acid proteases 3.
MHC-II molecules are formed in the endoplasmic reticulum with the help of the chaperone calnexin 4 and are held ready by the invariant chain li ; the complex is later fused with the HLA-DM DM right lower inset in panel B.
A Comprehensive Review of Structure and Function
The MHC molecule loaded with peptide is transported 9 and expressed on the cell surface Figure 7. Reproduced with permission from Bellanti, JA Ed. Donate Now. TB or not TB: a confusing case A 7 year old with severe muscle weakness and difficulty walking Why can I not walk today? Defaulted treatment 25 year old female presents with persistent flu-like symptoms Gastrointestinal Disorders A case of persistent bloody diarrhoea Hypersensitivity A case of acute fever, rash and vomiting Adverse event following routine vaccination Malignancies A case of cough, wasting and lymphadenopathy A case of lymphadenopathy and night sweats Case of enlarged hard tongue In the Red Mother to Child Transmission A high risk pregnancy Primary Immunodeficiencies A four year old with immunodeficiency Young girl with recurrent history of mycobacterial disease Immunodeficiency and failure to thrive Case of recurrent infections An 8 year old boy with recurrent respiratory infections 4 year old boy with recurrent bacterial infections Secondary Immunodeficiencies Is this treatment failure or malnutrition Immunology The Basics of the Immune System 1.
A Snapshot of the Immune System 2. Ontogeny of the Immune System 3. The Innate Immune System 4. Overview of T Cell Subsets 6. Transplantation 2. Immune Regulation in Pregnancy 4. Inflammation and autoinflammation 9.
Role of Human Leukocyte Antigens (HLA) in Autoimmune Diseases | SpringerLink
T cell mediated autoimmune diseases Antibody-mediated autoimmune diseases Special Focus Area 1. Primary Immunodeficiencies 2. Immunity to TB 4. Immunity to Malaria 5. Immunity to HIV 6. Thymic T Cell Development 7. Systems Vaccinology 2. Vaccine Development 3. Adjuvants 4. DNA Vaccines 5. Mucosal Vaccines 6. Infant Immunity and Vaccines 2. MHC class II molecules bind to peptides that are derived from proteins degraded in the endocytic pathway. Later, the CLIP is exchanged for an antigenic peptide derived from a protein degraded in the endosomal pathway.
Different MHC class II alleles can be used as genetic markers for several autoimmune diseases, possibly owing to the peptides that they present. Register Log in.
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Major Histocompatibility Complex
Figure 1. The MHC class I antigen-presentation pathway. Figure 2. Related Articles T Lymphocyte Transmigration. T-cell activation.
Related HLA Class II Antigens: A Comprehensive Review of Structure and Function
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