Invariant chain distinguishes between the exogenous and endogenous antigen presentation pathways

Class I MHC molecules acquire peptides from endogenously synthesized proteins, whereas class II antigens present peptides derived from extracellular compartment molecules. This dichotomy is due to the fact that the invariant chain associates with class II molecules in the endoplasmic reticulum, preventing binding of endogenous peptides. The mutually exclusive binding of peptide and invariant chain to class II molecules suggests that the invariant chain might play a part in autoimmune disease.     

Processing pathways for presentation of cytosolic antigen to MHC class II-restricted T cells.

Antigens presented to CD4+ T cells derive primarily from exogenous proteins that are processed into peptides capable of binding to class II major histocompatibility complex (MHC) molecules in an endocytic compartment. In contrast, antigens presented to CD8+ T cells derive mostly from proteins processed in the cytosol, and peptide loading onto class I MHC molecules in an early exocytic compartment is dependent on a transporter for antigen presentation encoded in the class II MHC region. Endogenous cytosolic antigen can also be presented by class II molecules. Here we show that, unlike class I-restricted recognition of antigen, HLA-DR1-restricted recognition of cytosolic antigen occurs in mutant cells without a transporter for antigen presentation. In contrast, DR1-restricted recognition of a short cytosolic peptide is dependent on such a transporter. Thus helper T-cell epitopes can be generated from cytosolic antigens by several mechanisms, one of which is distinct from the classical class I pathway.     

Proteolysis, proteasomes and antigen presentation.

Proteins presented to the immune system must first be cleaved to small peptides by intracellular proteinases. Proteasomes are proteolytic complexes that degrade cytosolic and nuclear proteins. These particles have been implicated in ATP-ubiquitin-dependent proteolysis and in the processing of intracellular antigens for cytolytic immune responses.     

Beta 2-microglobulin restriction of antigen presentation.

Antigens are generally thought to be recognized by cytotoxic T lymphocytes as peptides in the context of class I major histocompatibility proteins complex, which are heterodimers of heavy chains noncovalently associated with beta 2-microglobulin (beta 2m). The highly polymorphic nature of the heavy chains and their resulting ability to present different sets of peptides has presumably evolved to allow potent immune responses against most pathogens. By contrast, the polymorphism of beta 2m is limited; seven alleles are known in the mouse and only one has been identified in humans. beta 2-Microglobulin was consequently thought to have only structural functions: namely, to ensure correct folding of class I molecules and their transport to the cell surface. Although beta 2m is not implicated directly in the formation of the peptide binding site, we report here that it participates in the selection of MHC class I molecule-associated peptides.     

Thymic cortical epithelial cells lack full capacity for antigen presentation

Several recent studies have suggested that interactions between thymocytes and thymic stromal cells are essential for the development and elimination of antigen-reactive T lymphocytes. It is important, therefore, to characterize the stromal cells involved in presentation of antigen in the thymus. In a previous report, we demonstrated, using T-cell hybridomas, that three distinct types of antigen presenting cells in the thymus (cortical epithelial cells, macrophages, and dendritic cells) constitutively expressed self haemoglobin/Ia complexes. Here we report that one of these cell types, the cortical epithelial cell, does not induce stimulation of T-lymphocyte clones even though the antigen/Ia complex required for antigen-specific recognition is present. This lack of response occurs with both TH1 and TH2 clones. Responsiveness of the TH2 clone can be restored by adding the murine lymphokine interleukin-1 beta to the culture system.     

Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen

Cytotoxic T lymphocytes (CTLs) are thought to detect viral infections by monitoring the surface of all cells for the presence of viral peptides bound to major histocompatibility complex (MHC) class I molecules. In most cells, peptides presented by MHC class I molecules are derived exclusively from proteins synthesized by the antigen-bearing cells. Macrophages and dendritic cells also have an alternative MHC class I pathway that can present peptides derived from extracellular antigens; however, the physiological role of this process is unclear. Here we show that virally infected non-haematopoietic cells are unable to stimulate primary CTL-mediated immunity directly. Instead, bone-marrow-derived cells are required as antigen-presenting cells (APCs) to initiate anti-viral CTL responses. In these APCs, the alternative (exogenous) MHC class I pathway is the obligatory mechanism for the initiation of CTL responses to viruses that infect only non-haematopoietic cells.     

Class II MHC molecules can use the endogenous pathway of antigen presentation

Models for antigen presentation have divided the world of antigens into two categories, endogenous and exogenous, presented to T cells by class I and class II major histocompatibility complex (MHC) encoded molecules, respectively. Exogenous antigens are though to be taken up into peripheral endosomal compartments where they are processed for binding to class II MHC molecules. Endogenous antigens are either synthesized or efficiently delivered to the cytoplasm before being partially degraded in an as yet undefined way, and complexed with class I MHC molecules. A useful phenotypic distinction between the two pathways has been the sensitivity to weak bases, such as chloroquine, which is a property only of the exogenous pathway. The fungal antibiotic brefeldin A (BFA), which blocks protein transport from the endoplasmic reticulum to the Golgi network, also blocks class I-restricted antigen-presentation, providing us with the corresponding marker of the endogenous pathway. Experiments with influenza virus antigens have supported the view that class II MHC molecules can present exogenous but not endogenous antigen, whereas the observation that class II MHC molecules present measles virus non-membrane antigens by a chloroquine-insensitive pathway suggests that this is not always the case. We show here that influenza A matrix protein can be effectively presented to class II-restricted T cells by two pathways: one of which is chloroquine-sensitive, BFA-insensitive, the other being chloroquine-insensitive and BFA-sensitive. Our results indicate that both class I and class II molecules can complex with antigenic peptides in a pre-Golgi compartment and favour a unified mechanism for MHC-restricted endogenous antigen presentation.     

Co-localization of molecules involved in antigen processing and presentation in an early endocytic compartment

The pathways of intracellular traffic involved in antigen processing and presentation have been defined by immunoelectron microscopy. The export pathway for class II histocompatibility molecules and the antigen import pathway meet in a peripheral endocytic compartment having all the molecular machinery believed to be required for antigen processing and presentation, including internalized surface immunoglobulins, proteolytic enzymes and invariant chains. This compartment defines a site where peptides from endocytosed antigen can bind class II molecules en route to the cell surface for presentation to T cells.     

Brefeldin A implicates egress from endoplasmic reticulum in class I restricted antigen presentation

Most antigens must be processed intracellularly before they can be presented, in association with major histocompatibility complex (MHC) molecules at the cell surface, for recognition by the antigen-specific receptor of T cells. This processing appears to involve cleavage of protein antigens to smaller peptides. Only certain fragments of any protein can serve as T-cell epitopes and this is, at least in part, determined by the requirement that peptides be able to bind the MHC molecules. Class I restricted antigens are derived from proteins, such as viral antigens, that are synthesized within the presenting cell. Many of these antigens are cytosolic proteins and recent evidence suggests that it is in the cytosol that these proteins are processed to produce either the antigenic peptides or processed intermediates. How and where these processed cytosolic antigens cross the membrane of the vacuolar system and bind to the extracellular domain of the class I molecule is not known but one obvious site for this process is the endoplasmic reticulum (ER), because this organelle is specialized to translocate proteins across the membrane from the cytosol into the secretory system. Based on this model, we reasoned that if we could pharmacologically block the movement of proteins out of the ER, endogenous antigen presentation would cease. An agent which causes such an effect is available--the fungal antibiotic Brefeldin A (BFA). Consistent with the above hypothesis, we report that BFA completely abolishes the ability of a cell to present endogenously synthesized antigens to class I restricted cytotoxic T cells.     

Restoration of antigen presentation to the mutant cell line RMA-S by an MHC-linked transporter.

In mammalian cells, short peptides derived from intracellular proteins are displayed on the cell membrane associated with class I molecules of the major histocompatibility complex (MHC). The surface presentation of class I-peptide complexes presumably alerts the immune system to intracellular viral protein synthesis. Peptides derived from the cytosol must reach the cisternae of the endoplasmic reticulum where they are required for the assembly of stable class I molecules, and it has been proposed that the products of the two MHC-encoded ATP-binding cassette (ABC) transporter genes function to deliver the peptides across the membrane of the endoplasmic reticulum. This idea is supported by experiments in which transfection of a human cell line defective in class I expression with a complementary DNA of one of these genes restored cell surface expression levels. Here we show that the complete phenotype of the mouse mutant cell line RMA-S, in which lack of surface expression of stable class I molecules correlates with an inability to present viral peptides originating in the cytosol, is repaired by the cDNA of the other transporter gene. These results are consistent with the possibility that the two transporter polypeptides form a heterodimer.     

Proteasome subunits encoded by the major histocompatibility complex are not essential for antigen presentation.

Major histocompatibility complex (MHC) class I molecules bind and deliver peptides derived from endogenously synthesized proteins to the cell surface for survey by cytotoxic T lymphocytes. It is believed that endogenous antigens are generally degraded in the cytosol, the resulting peptides being translocated into the endoplasmic reticulum where they bind to MHC class I molecules. Transporters containing an ATP-binding cassette encoded by the MHC class II region seem to be responsible for this transport. Genes coding for two subunits of the '20S' proteasome (a multicatalytic proteinase) have been found in the vicinity of the two transporter genes in the MHC class II region, indicating that the proteasome could be the unknown proteolytic entity in the cytosol involved in the generation of MHC class I-binding peptides. By introducing rat genes encoding the MHC-linked transporters into a human cell line lacking both transporter and proteasome subunit genes, we show here that the MHC-encoded proteasome subunit are not essential for stable MHC class I surface expression, or for processing and presentation of antigenic peptides from influenza virus and an intracellular protein.     

Competition for antigen presentation in living cells involves exchange of peptides bound by class II MHC molecules

T cells recognize foreign proteins as peptides bound to self molecules encoded by the major histocompatibility complex (MHC). The kinetics of interaction between purified class II MHC molecules and peptides is unusual, in that the rate of association is very slow, but once formed, the complexes are extremely stable. This raises the question of how the antigen-presenting cell provides a sufficient number of free MHC binding sites to ensure T cell immunity. We present results suggesting that an exchange of peptide in MHC binding sites may take place under physiological conditions.     

A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway

Major histocompatibility complex (MHC) class I molecules export peptides to the cell surface for surveillance by cytotoxic T lymphocytes. Intracellular peptide binding is critical for the proper assembly and transport of class I molecules. This mechanism is impaired as a result of a non-functional peptide supply factor gene (PSF) in several human mutant cell lines with genomic lesions in the MHC. We have now identified PSF in the MHC class II region by deletion mapping in mutants and chromosome-walking. PSF is homologous to mammalian and bacterial ATP-dependent transport proteins, suggesting that it operates in the intracellular transport of peptides.     

Signalling through the MHC class II cytoplasmic domain is required for antigen presentation and induces B7 expression.

Class II major histocompatibility complex (MHC) molecules function as antigen-presenting elements as well as signal transducers on B lymphocytes. We previously reported that a B lymphoma cell transfectant, 5C2, expressing genetically engineered I-Ak molecules with truncated cytoplasmic domains was severely impaired in both antigen presentation and in anti-Ia-induced intracytoplasmic signalling. These two functions could be restored by preculturing 5C2 cells with cyclic AMP analogues. Here we demonstrate that impaired signal transduction by truncated class II molecules results in a deficiency in induction of the newly defined B-cell accessory molecule B7 (ref. 8), which can be reversed by restoration of B7 expression. These data imply that contact of the T-cell antigen receptor with MHC/antigen ligand results in signal transmission through the class II cytoplasmic domain. This signal, which can be mimicked by dibutyryl cAMP, induces expression of B7, resulting in effective antigen presentation. The fact that crosslinking of surface class II MHC also induces B7 expression on normal resting human B cells supports this contention.     

Tyrosine-containing motif that transduces cell activation signals also determines internalization and antigen presentation via type III receptors for IgG.

Type III receptors for IgG (Fc gamma RII; ref. 1), high-affinity IgE receptors (Fc epsilon RI; ref. 2), as well as the T- and B-cell antigen receptors, consist of multiple components with specialized ligand-binding and signal transduction functions. Fc gamma RII alpha (ligand-binding) and gamma (signal-transducing) subunits are expressed in macrophages, a cell type involved in the uptake of antigen, its processing and the presentation of the resulting peptides to major histocompatibility complex class II-restricted T lymphocytes. Here we show that murine Fc gamma RIII, transfected into Fc gamma R-negative antigen-presenting B-lymphoma cells, mediate rapid ligand internalization and strongly increase the efficiency of antigen presentation when antigen is complexed to IgG. Efficient internalization and antigen presentation via Fc gamma RIII did not require the cytoplasmic domain of the ligand-binding alpha-chain, but did require the gamma-subunit. Using chimaeric molecules, we show that gamma-chain contains a signal for receptor internalization and that the mutation of either of the two tyrosine residues present in its cytoplasmic domain prevents efficient internalization and antigen presentation of immune complexes. Thus, associated chains and their tyrosine-containing motif are not exclusively involved in cell activation, but also determine multimeric receptor internalization.     

PowerPoint演示文稿中的超级链接

系统阐述了PowerPoint演示文稿的结构方式和超级链接的作用、分类与选型，同时提出了有痕超级链接和无痕超级链接，并扼要说明了其创建过程，以期指导教师PowerPoint演示文稿的制作实践。     

京口旗营述略

京口旗营是古城镇江城市发展中的一个特殊产物,它从初到盛,从盛到衰,最后在辛亥革命的大潮中被解体,经历了一个漫长的历史过程,贯穿于清朝始终。由于它的存在,镇江城区中有了特殊的＂城中城＂,出现了满族、蒙古族同汉族之间相互影响、相互共存的局面。