High efficiency of endogenous antigen presentation by MHC class II molecules (original) (raw)
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Presentation of Cytosolic Antigens Via MHC Class II Molecules
Immunologic Research, 2004
Major histocompatibility (MHC) class II molecules function to present antigenic peptides to CD4 T lymphocytes. The pathways by which these molecules present exogenous antigens have been extensively studied. However by contrast, far less is known about the processing and trafficking of cytosolic antigens, which can also serve as an alternative source of ligands for MHC class II molecules. Self-proteins, tumor antigens, as well as viral proteins found within the cytosol of cells, can be presented via MHC class II molecules, resulting in the activation of specific CD4 T cells. Studies have begun to reveal unique steps as well as some similarities in the pathways for cytosolic and exogenous antigen presentation. Recent developments in this area are summarized here.
The Journal of Immunology, 2001
Peptides from extracellular proteins presented on MHC class II are mostly generated and loaded in endolysosomal compartments, but the major pathways responsible for loading peptides from APC-endogenous sources on MHC class II are as yet unclear. In this study, we show that MHC class II molecules present peptides from proteins such as OVA or conalbumin introduced into the cytoplasm by hyperosmotic pinosome lysis, with efficiencies comparable to their presentation via extracellular fluid-phase endocytosis. This cytosolic presentation pathway is sensitive to proteasomal inhibitors, whereas the presentation of exogenous Ags taken up by endocytosis is not. Inhibitors of nonproteasomal cytosolic proteases can also inhibit MHC class II-restricted presentation of cytosolically delivered protein, without inhibiting MHC class I-restricted presentation from the same protein. Cytosolic processing of a soluble fusion protein containing the peptide epitope I-E␣ 52-68 yields an epitope that is similar to the one generated during constitutive presentation of I-E␣ as an endogenous transmembrane protein, but is subtly different from the one generated in the exogenous pathway. Constitutive MHC class II-mediated presentation of the endogenous transmembrane protein I-E␣ is also specifically inhibited over time by inhibitors of cytosolic proteolysis. Thus, Ag processing in the cytoplasm appears to be essential for the efficient presentation of endogenous proteins, even transmembrane ones, on MHC class II, and the proteolytic pathways involved may differ from those used for MHC class I-mediated presentation.
New tools for antigen delivery to the MHC class I pathway
Trends in Immunology, 2004
At the beginning of this new millennium, pathogens and cancer remain the leading causes of death worldwide. The development of vaccines to prevent diseases for which no vaccine currently exists, such as AIDS or malaria, or to treat chronic infections or cancers, as well as the improvement of efficacy and safety of existing vaccines, remains a high priority. In most cases, the development of such vaccines requires strategies capable of stimulating CD8 1 cytotoxic T lymphocytes (CTLs) and thus, to deliver antigen to MHC class I molecules. There exists several different pathways for loading antigenic peptides onto MHC class I molecules, either based on the endogenous cytosolic MHC I pathway or on cross-presentation. The understanding of the relevance of each of these mechanisms in CTL activation will help vaccine design to progress more rationally.
Journal of Cell Science, 2004
The location of antigens in distinct intracellular compartments of antigen-presenting cells (APCs) influences their proteolytic processing as well as access to major histocompatibility complex (MHC) molecules and presentation to T cells. MHCI and MHCII molecules are directed to different intracellular compartments for sampling peptide antigens (Neefjes et al., 1990; Peters et al., 1991). It is probable that pathways by which MHC molecules acquire peptides will have a significant impact on generation of peptide diversity that will be ultimately sensed by the T cell receptor. Thus, understanding the pathways involved in peptide generation and loading is an extremely important issue from an immunological perspective. This is especially relevant for the dissection of the mechanism of generation of an immune response against foreign proteins and development of tolerance against self proteins. Peptides generated in the cytosol by proteasomal degradation are generally thought to be presented on MHCI. These peptides are first transported across the endoplasmic reticulum (ER) membrane by the transporter associated with presentation (TAP), for loading on to MHCI in the ER lumen (Rock and Goldberg, 1999; York and Rock, 1996). Peptide-MHCI interaction is expected to take place during MHCI assembly, and is required for MHCI export out of the ER (Cresswell et al., 1999). In contrast, the generation and loading of peptides on MHCII molecules which present to the other class of T cells, namely the CD4 T cells, is believed to take place in endosomes and involves peptides derived from proteins and other antigens delivered from the outside via endocytic mechanisms. The apparent dichotomy between the sources of peptides for loading onto MHCI and MHCII is reinforced because newly synthesized MHCII molecules are protected from peptide loading in the ER and Golgi by the invariant chain (Ii) (Cresswell, 1994; Cresswell, 1996) which also sorts associated MHCII molecules from the Golgi to endolysosomal compartments (Bakke and Dobberstein, 1990). Immunocytochemistry, subcellular fractionation and immunoelectron microscopy approaches have identified MIIC or CIIVs as the canonical loading compartments for newly synthesized MHC class II (Neefjes, 1999; Peters et al., 1991). These are sites where MHCII molecules accumulate, and it is often argued that MIICs (or CIIVs) are a collection of late endocytic compartments that contain the necessary proteins for efficient peptide loading of MHCII molecules (Geuze, 1998; Neefjes, 1999). It is in the acidic milieu of these endosomal compartments that Ii-peptide exchange is facilitated by the endosomally localized peptide exchange catalyst H-2M in mice or HLA-DM in humans (Martin et al., 1996; Miyazaki et al., 1996). Peptide-MHCII complexes may also be generated when cell surface MHCII molecules recycle 4219 Antigen-presenting cells (APCs) are expected to present peptides from endocytosed proteins via major histocompatibility complex (MHC) class II (MHCII) molecules to T cells. However, a large proportion of peptides purified from MHCII molecules are derived from cytosolic self-proteins making the pathway of cytosolic peptide loading onto MHCII of critical relevance in the regulation of immune self-tolerance. We show that peptides derived from cytoplasmic proteins either introduced or expressed in the cytoplasm are first detectable as MHCIIpeptide complexes in LAMP-1 + lysosomes, prior to their delivery to the cell surface. These peptide-MHC complexes are formed in a variety of APCs, including peritoneal macrophages, dendritic cells, and B cells, and are able to activate T cells. This process requires invariant chain (Ii)-dependent sorting of MHCII to the lysosome and the activity of the molecular chaperone H-2M. This pathway is independent of the ER resident peptide transporter complex TAP and does not take place by cross-presentation from neighbouring cells. In conjunction with our earlier results showing that these peptides are derived by cytosolic processing via the proteasome, these observations provide evidence for a ubiquitous route for peptide transport into the lysosome for the efficient presentation of endogenous and cytoplasmic proteins to CD4 T cells.
The ins and outs of MHC class II-mediated antigen processing and presentation
MHC class II-restricted antigen presentation is essential for CD4 + T cell-dependent immune responses. Different professional antigen-presenting cells (APCs) participate in a wide range of processes that are necessary for the generation of an effective and specific immune response. Dendritic cells (DCs) sample their environment and capture foreign antigens, such as those derived from bacteria or viruses, and initiate adaptive immune responses against these antigens by activating CD4 + and CD8 + T cells 1 . DCs and epithelial cells in the thymus express (and also capture) numerous self proteins and contribute to central tolerance and peripheral tolerance. By contrast, each B cell generally captures a single antigen after binding to its antigen-specific surface B cell receptor (BCR) 2 and then presents peptides from this antigen to specific T cells. Regardless of APC type, all APCs specifically interact with distinct subsets of T cells that express antigen-specific T cell receptors (TCRs) on their surface. The specificity of this interaction depends on the ability of APCs to display antigenic peptides, immobilized by MHC class I and class II molecules, on their surface. MHC class II binds antigenic peptides that are generated by proteolysis of self and non-self proteins in endosomes and lysosomes, and 'presents' them to antigen-specific CD4 + T cells 3 . Recognition of peptide-MHC class II by CD4 + T cells stimulates their activation and differentiation into T helper cell subsets Abstract | Antigenic peptide-loaded MHC class II molecules (peptide-MHC class II) are constitutively expressed on the surface of professional antigen-presenting cells (APCs), including dendritic cells, B cells, macrophages and thymic epithelial cells, and are presented to antigen-specific CD4 + T cells. The mechanisms of antigen uptake, the nature of the antigen processing compartments and the lifetime of cell surface peptide-MHC class II complexes can vary depending on the type of APC. It is likely that these differences are important for the function of each distinct APC subset in the generation of effective adaptive immune responses. In this Review, we describe our current knowledge of the mechanisms of uptake and processing of antigens, the intracellular formation of peptide-MHC class II complexes, the intracellular trafficking of peptide-MHC class II complexes to the APC plasma membrane and their ultimate degradation.
Traffic, 2000
Exogenous antigenic peptides captured and presented in the context of major histocompatibility (MHC) class II molecules on APC, have been employed as potent vaccine reagents capable of activating cellular immune responses. Binding and presentation of select peptide via surface class II molecules has been reported. Here, a role for endocytosis and early endosomes in the presentation of exogenous peptides via MHC class II molecules is described. T cell recognition of a 14 amino acid human serum albumin-derived peptide in the context of HLA-DR4 was observed only with metabolically active APC. The delayed kinetics and temperature dependence of functional peptide presentation via APC, were consistent with a requirement for peptide internalization to early endosomal compartments prior to T cell recognition. Ablating endocytosis by exposing cells to inhibitors of ATP production completely blocked the display of functional peptide:class II complexes on the surface of the APC. Presentation of the peptide was also found to be sensitive to primaquine, a drug that perturbs the recycling of transport vesicles containing endocytic receptors and mature class II complexes. Functional presentation of the endocytosed peptide was dependent upon these mature class II complexes, as inhibitor studies ruled out a requirement for newly synthesized class II molecules. N-terminal processing of the endocytosed peptide was observed upon trafficking through endosomal compartments and linked to the formation of functional peptide:class II complexes. These findings establish a novel mechanism for regulating class II-restricted peptide presentation via the endocytic pathway.