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Chapter 12 : Antigen Processing and Presentation

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Abstract:

This chapter covers antigen-processing cells, processing and presentation of: proteins produced within a host cell, proteins brought into a host cell via endocytosis, and nonprotein antigens, and bacterial and viral strategies to evade the antigen-processing pathways. A variety of antigen-presenting cells (APCs) have been identified in which dendritic cells, macrophages, and B cells are the major ones. Each of these differs in important ways and in their properties, and one of the most important is the endogenous and inducible level of costimulatory signals that affect the relative potency of the different types of APCs. The basic division of pathways holds up in a number of instances and can be experimentally demonstrated by use of selective variants of a given antigen. One of the major functions of CD8 T cells responding to antigenic peptides presented by major histocompatibility complex (MHC) class I molecules is to kill via a cytotoxic activity the cell that is presenting the antigen. The role of the immunoproteasome in antigen processing, presentation, and T-cell development has been demonstrated by the use of biochemical inhibitors of proteasome catalytic function and in transgenic knockout mice. The MHC class II antigen-processing pathway, unlike that of MHC class I, is generally intended to present antigens obtained by endocytosis from the extracellular milieu, although some cytosolic proteins are shunted into this processing pathway.

Citation: Wetzler L. 2004. Antigen Processing and Presentation, p 283-296. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch12

Key Concept Ranking

MHC Class I
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MHC Class II
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Viral Proteins
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Figures

Image of Figure 12.1
Figure 12.1

Antigen-processing pathways. The endogenous pathway utilized by most cells. Proteins are produced within the cellular cytosol on polyribosomes. These are then shunted to the immunoproteasome for degradation. The source of proteins can either be those tagged for degradation or defective ribosomal products. Peptides generated by the immunoproteasome are then made available to the MHC class I peptides for presentation. The exogenous pathway utilized by APC. Antigens are taken up by phagocytosis/endocytosis or pinocytosis and shunted into early endosomes. These mature into late endosomes that will fuse with vesicles containing MHC class II proteins, where the two will be brought together and be transported to the surface of the APC. Mechanisms of cross-presentation. Exogenous antigens can enter a cell by endocytosis or pinocytosis or by invading the cell and replicating in the cytosol. Exogenous antigens can be shunted to the cytosol for processing via the immunoproteasome. Alternately, peptide fragments of the exogenous antigen can be fused with vesicles containing recycled MHC class I proteins and placed within the antigen-binding groove. Reprinted from M. Larsson et al., 141–148, 2001, with permission.

Citation: Wetzler L. 2004. Antigen Processing and Presentation, p 283-296. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch12
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Image of Figure 12.2
Figure 12.2

Structure of the proteasome. The 26S proteasome is thought to provide peptides for the majority of antigen presentation functions. It consists of the 20S core (red, blue, and green) and a 19S regulatory subunit (pink and orange). The 20S proteasome is a tube-shaped complex consisting of two rings of “a” subunits (green) and two rings of “b” subunits (blue and red). The 19S regulatory subunit binds to the 20S proteasome and influences the substrate specificity of the proteasome (e.g., by binding to proteins that have been conjugated to the protein ubiquitin). Assembly of the immunoproteasome. An immunoproteasome is formed by an initial seven-membered _ ring that provides places for the 7-membered β ring to bind. In the immunoproteasome, the subunits β (LMP-2), β (LMP-7), and β (LMP-10) replace three of the normally occurring β subunits (β, β, and β are shown in red). LMP-2 and LMP-7 are thought to modulate the fine specificity of the proteasome to preferentially produce peptides that can bind to the MHC class I-binding groove. A proteasome maturation protein (POMP) along with chaperones (C) facilitates polymerization into a large assembly, followed by autocatalytic activation of the 20S subunit. Two copies of the PA28 activator, which is thought to alter the specificity of the proteasome by assisting in the unfolding of particularly large substrate proteins, are attached to form the final 20S-PA28 immunoproteasome complex.

Citation: Wetzler L. 2004. Antigen Processing and Presentation, p 283-296. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch12
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Image of Figure 12.3
Figure 12.3

Diagram of TAP. TAP is a heterodimer of two polypeptides called TAP1 and TAP2. Both of the polypeptides are members of the ATP-binding cassette family of transporter proteins. The cytosolic nucleotide-binding domains (NBD) bind and hydrolyze ATP to provide energy to drive the transporter function of TAP.

Citation: Wetzler L. 2004. Antigen Processing and Presentation, p 283-296. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch12
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Image of Figure 12.4
Figure 12.4

Schematic diagram of the assembly of MHC class I peptide cleavage by the proteasome, and peptide transport by TAP. The diagram also shows the loading of endogenous peptide antigens onto MHC class I within the ER and highlights the role in this process of the chaperone proteins calnexin, calreticulin, and tapasin. Export of MHC class I-peptide complexes to the cell surface allows these complexes to be presented to CD8 T cells.

Citation: Wetzler L. 2004. Antigen Processing and Presentation, p 283-296. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch12
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Image of Figure 12.5
Figure 12.5

Synopsis of immune evasion mechanisms employed by viruses to avoid presentation by MHC class I. The EBV EBNA-1 protein and the HSV ICP47 protein can both interfere with the normal function of TAP. CMV interferes with MHC class I surface expression through the US3 protein, which retains MHC class I in the ER; the gp40 protein, which retains MHC class I in the Golgi complex; the US6 protein, which prevents peptide translocation by TAP; and the US2 and US11 proteins, which induce translocation of MHC class I molecules from the ER into the cytosol.

Citation: Wetzler L. 2004. Antigen Processing and Presentation, p 283-296. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch12
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Image of Figure 12.6
Figure 12.6

Schematic diagram showing the route by which exogenous antigens are processed and presented and MHC class II proteins produced. MHC class II proteins are synthesized in the ER, processed through the Golgi complex, and then membrane vesicles bud off to produce the compartments (MIICs) where the invariant chain is bound to MHC class II and digested to leave only the CLIP peptides behind. The Ii serves a chaperone function, aiding in the assembly of MHC class II in the ER and simultaneously preventing the premature association of endogenous peptides with MHC class II while the latter resides in the ER. Ii also provides targeting signals, ensuring the trafficking of MHC class II to the MIIC. Following fusion of the MHC transport vesicles with phagolysosomes, the CLIP peptide is removed from the MHC class II and exogenous antigenic peptides loaded into the antigen-binding grooves. This complex then moves to the cell surface for interacting with CD4 T cells.

Citation: Wetzler L. 2004. Antigen Processing and Presentation, p 283-296. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch12
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Image of Figure 12.7
Figure 12.7

The MHC class II-like proteins HLA-DM and HLA-DO modulate the interaction of MHC class II with antigenic peptide. HLA-DM helps MHC class II bind antigenic peptides by triggering the removal of CLIP from MHC class II. Whether this occurs by the direct removal of CLIP by HLA-DM or indirectly by conformational shifts induced in MHC class II by HLA-DM is not yet known. HLA-DO negatively regulates HLA-DM-mediated peptide exchange. HLA-DO associates with HLA-DM, and HLA-DM–HLA-DO complexes demonstrate a lower ability to mediate peptide exchange than HLA-DM alone.

Citation: Wetzler L. 2004. Antigen Processing and Presentation, p 283-296. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch12
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Image of Figure 12.8
Figure 12.8

Synopsis of immune evasion strategies employed by bacteria to prevent presentation of bacterial antigens on MHC class II. Shigellae and listeriae have the ability to escape from an endosome before acidification and lysosome fusion. species and mycobacteria alter the phagosomes in which they reside by inhibiting endosome acidification and/or preventing endosome-lysosome fusion. Leishmanias permit normal endosome acidification and endosome- lysosome fusion but prevent antigen presentation by trapping MHC class II molecules in these vesicles.

Citation: Wetzler L. 2004. Antigen Processing and Presentation, p 283-296. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch12
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Image of Figure 12.9
Figure 12.9

Diagram showing the route by which microbial lipid antigens (orange) are internalized, processed in phagolysosomes, and presented on CD1 molecules (red) to T cells. The diagram also shows the trafficking of CD1 starting from its point of synthesis in the ER, proceeding to the late endosomal compartment where CD1 encounters processed lipid antigen. The dotted arrows labeled with question marks indicate that some members of the CD1 family (e.g., CD1a) likely do not traffic to the late endosomes and therefore bind antigenic lipids in another, unknown subcellular compartment.

Citation: Wetzler L. 2004. Antigen Processing and Presentation, p 283-296. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch12
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References

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