Antigen processing and presentation represent the hallmark of the adaptive immune response. This complex mechanism of antigen recognition begins with antigens that become associated with self-MHC molecules for presentation to T cells with appropriate receptors. Proteins from exogenous anti gens, such as bacteria, are internalized by the APC (dendritic cells or macrophages) and undergo denaturation or partial proteolysis in the endocytic vesicles within the APC. While in the endosomal compartment, these peptide fragments fuse with exocytic vesicles containing MHC class II molecules. As noted in Figure 1, this step exposes the appropriate linear peptide fragment that eventually becomes expressed on the surface of the APC (as the peptide-MHC complex).

Fig1. Antigen-processing pathways (MHC classes I and II). (Modified and reproduced with permission from Parslow TG, et al [editors]: Medical Immunology, 10th ed. McGraw-Hill, 2001. © The McGraw-Hill Companies, Inc.

The MHC class II molecules are synthesized in the rough endoplasmic reticulum (ER) and then they proceed out through the Golgi apparatus. The invariant chain, a poly peptide that helps transport the MHC molecules, complexes with the MHC class II complex in an endosome. This vesicle is called the MHC class II compartment. This invariant chain is useful and blocks the binding of self-endogenous cellular peptides into the MHC class II complex. The invariant chain is now enzymatically removed. Through a series of steps, the MHC class II binds exogenous antigen (peptide fragments) and is transported to the cell membrane for presentation.

The interaction of endogenous antigens within a virus infected cell and the MHC class I molecule is outlined in Figure 1. In brief, cytosolic proteins are broken down by a proteolytic complex called the proteasome. The cytosolic peptides gain access to nascent MHC class I molecules in the rough ER via the peptide transporter systems (TAPs). The TAP genes are also encoded in the MHC. Within the lumen of the ER, peptide antigens approximately 8–10 residues in length com plex with nascent MHC class I proteins and cooperate with β2-microglobulin to create a stable, fully folded MHC class I–peptide antigen complex that is then transported to the cell surface for display and recognition by CD8 cytotoxic T cells. The binding groove of the class I molecule is more constrained than that of the class II molecule, and therefore, shorter pep tides are found in class I than in class II MHC molecules. Once the cytotoxic T cell recognizes the MHC class I peptide anti gen, it can now kill the virus-infected cell.

Several viruses attempt to defeat the immune response by interfering with the antigen-processing pathways. For example, an HIV Tat protein is able to inhibit expression of class I MHC molecules. A herpesvirus protein binds to the TAPs, preventing transport of viral peptides into the ER, where class I molecules are being synthesized. A consequence of these inhibitory mechanisms is that the infected cells are not recognized by cytotoxic lymphocytes.

Some bacterial and viral antigens are able to activate large numbers of T cells through a special pathway. These proteins are called superantigens. Superantigens do not require processing and therefore are able to bind to MHC molecules outside the peptide-binding cleft (Figure 2B). Compared to the standard antigen-induced T-cell response where a small number of T cells are activated, superantigens can stimulate much larger numbers (~25% more) of the T cells. Classic examples of superantigens include certain bacterial toxins, including the staphylococcal enterotoxins, toxic shock syndrome toxin, and group A streptococcal pyrogenic exotoxin A. A consequence of this massive activation of T cells is the overproduction of cytokines, in particular, IFN-γ. IFN-γ in turn activates macrophages to produce IL-1, IL-6, and TNF-α, all which may contribute to a “cytokine storm” causing severe symptoms of shock and multiple organ failure.

Fig2. Binding of antigen by MHC and T-cell receptor (TCR). In panel A, a model of the interaction between peptide antigen, MHC, and the TCR is shown. The Vα and Vβ regions of the TCR are shown interacting with the α helices that form the peptide-binding groove of MHC. In panel B, a model of the interaction between a superantigen, MHC, and the TCR, is shown. The superantigen interacts with the Vβ region of the TCR and with class II MHC outside the peptide-binding groove. (Adapted with permission from Stites DG, et al [editors]: Medical Immunology, 9th ed. McGraw-Hill, 1997. © The McGraw-Hill Companies, Inc.)

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مواضيع ذات صلة

Antibody Structure and Function

B Cell Receptor for Antigen

Methods of Enhancing Agglutination

Mechanisms of Agglutination

The Major Histocompatibility Complex

Cellular Basis of the Adaptive Immune Response

Mechanisms of Innate Immunity

Overview of Acute-Phase Proteins

C-Reactive Protein

Hematopoietic Stimulators

The Complement System: Diagnostic Evaluation

Biological Functions of Complement Proteins