In order to initiate a specific immune response to an infectious agent, the immune system must be able to wade through the sea of molecules that are associated with pathogenic invasion and isolate particular protein products that will sharpen the efforts of host defense. Implicit to this model of counteraction is the processing of an immunogenic peptide epitope (antigen processing) and its presentation on the surface of a team of cells, referred to as APCs (Antigen Presenting Cells) (antigen presentation). The result of these actions is the induction of a T-cell response that recruits and engages the other molecular participants of the immune response. Antigen processing and presentation refer to the processes that occur within a cell that result in fragmentation (proteolysis) of proteins, association of the fragments with MHC (Major Histocompatibility Complex) molecules, and expression of the peptide-MHC molecules at the cell surface where they can be recognized by the TCR (T-Cell Receptor) on a T-Cell (Ref. 1). The TCR can recognize antigen only in the form of a peptide bound to an MHC molecule on a human cell surface. The antigens recognized by T-cells are peptides that arise from the breakdown of macromolecular structures, the unfolding of individual proteins and their cleavage into short fragments through antigen processing. The peptides must be bound by an MHC molecule and presented at the cell surface. At the core of this immune system element is the MHC. Located on human chromosome 6, the MHC is a highly polymorphic set of genes that encode for molecules essential to self/non-self discrimination and antigen processing and presentation. There are two classes of MHC molecules, MHC-I (MHC-Class I) and MHC-II (MHC-Class II). MHC-I and MHC-II molecules are both transmembrane glycoproteins belonging to the immunoglobulin supergene family. MHC-I molecules are composed of a transmembrane alpha chain associated non-covalently with the Beta2M (Beta2-Microglobulin) chain. MHC-I molecules are specialized for the presentation of peptides derived from endogenous proteins (intracellular antigens) to the TCR of CD8+ T-cells (CD8-expressing T-cells). MHC-II molecules are composed of two non-covalently linked transmembrane chains, called Alphaƒn (33 kD) and Betaƒn(29 kD). They are specialized for the presentation of extracellular antigens to the TCR of CD4+ T-cells (CD4-expressing T-cells) (Ref. 2, 3 & 4).

Endogenous/intracellular antigens are produced by viruses replicating within a nucleated host cell, processed by the proteolytic system acting on host intercellular proteins, and presented by MHC molecules. Intracellular proteins are cut into short peptides in the cell's multifunctional protease complex, the proteasome (Ref. 5). The proteasome is a large proteolytic complex that contains many subunits, including two subunits, LMP2 (Large Multifunctional Protease-2) and LMP7 (Large Multifunctional Protease-7), encoded within the MHC locus. Proteins bound for degradation are targeted to the proteasome by covalent linkage with a small protein known as ubiquitin. The two subunits of the proteasome, LMP2 and LMP7, induce the proteolytic complex to generate peptides that bind especially well to MHC-I molecules. The actual cleaving of protein occurs in the channel of the proteasome molecule. Peptides generated in the cytosol are then transported into the RER (Rough Endoplasmic Reticulum) to enable interaction with MHC molecules (Ref. 6). TAP (Transporters Associated with Antigen Processing) is a transmembrane heterodimeric protein that allows for the crucial step of peptide translocation. TAP trasnsports peptides into the ER (Endoplasmic Reticulum) that are ideally suited for binding with MHC-I molecules. The peptides consist of 8–13 amino acids. MHC-I molecules are tethered to the TAP transporter via a novel protein, tapasin. Peptides are then loaded onto the MHC-I molecule and transported to the cell surface for recognition by CD8+ T-cells (Ref. 7 & 8).

Exogenous/extracellular antigens are internalized by APCs such as macrophages, dendritic cells and B-cells. APCs can phagocytose and/or endocytose antigen, endosomally process it, and present it in association with MHC-II molecules (Ref. 8 & 9). Internalized antigen is processed within three increasingly acidic endosomal environments: early endosomes (pH 6.0–6.5), late endosomes (pH 5.0–6.0) and lysosomes (pH 4.5–5.0). Acid-dependent hydrolytic enzymes degrade antigen into peptides consisting of 13–18 amino acids. Class-II Alpha and Beta chains associate within the RER. A protein known as the Ii (Invariant Chain) binds to the peptide-binding cleft of the MHC-II molecule and thereby prevents its binding with endogenous antigens meant to be targeted to MHC-I molecules only. The Ii seems to provide other important functions for the MHC-II molecule, too. It is involved in the folding of Alpha and Beta chains, the exit of the complex from the ER, and its targeting to the endocytic compartments. The MHC-II-Ii complex is transported to early endosomes. Ii also functions to transport the Class-II heterodimer to the late endosomal compartments: MIICs (MHC-Class II Compartments) where MHC-II molecules are loaded with peptide. Once in the MIIC, Ii is degraded by proteases (Cathepsins) until only a small fragment called CLIP (Class II-associated Invariant Chain Peptide) remains associated with the peptide-binding cleft to prevent premature interaction with partially-processed antigen. In the lysosome, HLA-DM, a vesicle membrane protein, mediates the removal of CLIP and the binding of antigen to MHC-II. The MHC-II-Antigen complex then moves to the plasma membrane where the neutral environment stabilizes it. At the cell surface, antigen is presented to CD4+ T-cells (Ref. 8 & 10).



Pathway Key

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