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CHaPter 6 Overview of T-Cell Recognition 101

complexes, subcapsulary macrophages can bind and capture Viral infection can activate and increase autophagy, thus
antigenic material and transfer it across the subcapsulary sinus. increasing the potential the ability of MHC class II molecules
For antigen presentation, B cells must extract the antigen from to sample cytosolic viral proteins for presentation of their derived
the presenting APC surface. This extraction of cell-associated peptides. Viral antigens, such as Epstein-Barr virus (EBV)–nuclear
antigen may involve localized protease secretion and/or myosin antigen 1 and the Mycobacterium tuberculosis antigen Ag85B,
mediated pulling forces that allow invagination of antigen- have been shown to be presented via this pathway, allowing
containing membranes. Ig-mediated uptake of antigen enhances immune detection. Interestingly, a number of viruses have been
the ability of B cells to acquire low concentrations of antigen, shown to antagonize specific components involved in autophagy
providing a way to discriminate B cells with high affinity versus and thus evade immune surveillance.
low affinity for antigen, and it also directly signals to the B cells.
Signal transduction through the BCR is typically initiated by KeY ConCePtS
cross-linking of Ig from multivalent antigens (Chapter 4). Rear- Antigen Presentation by Major Histocompatibility
rangement of endosomal compartments following signal Complex (MHC) Class I Molecules
transduction promotes antigen processing and efficient recogni-
tion of the antigen-derived peptides by CD4 T cells. • Proteolysis for MHC class I–restricted presentation is typically the
After uptake, the antigen–Ig complex is delivered to late function of the proteasome, which is found in the cytosol.
endosomal compartments where the more mild proteolytic • Peptides are imported through the endoplasmic reticulum (ER)
compartments prevent terminal degradation of the antigen. MHC membrane by the TAP (for transporter associated with antigen process-
ing) transmembrane channel.
class II synthesis and transport to these compartments allows • Peptide binding to class I within the ER is orchestrated by a large
for peptide–class II epitope display. The capture of antigen by multiprotein complex termed the peptide-loading complex.
the Ig receptor is an essential feature of the ability of the B cell • Tapasin serves as an adaptor between TAP and MHC class I molecules,
to obtain CD4 T-cell help. Note that to recruit CD4 help, the and it edits the peptide repertoire presented by MHC class I for
antigen recognized by the B cell must be physically attached, by recruitment of CD8 T cells.
either covalent or strong noncovalent interactions, to the antigen
that will elicit CD4 T-cell help. The cognate-nature B cell–CD4 MHC Class I–Restricted Antigen Presentation
T cell help, which requires linkage of CD4 T-cell and B-cell The classical pathway of MHC class I–restricted antigen presenta-
epitopes, is key to vaccine strategies. It underlies the creation of tion involves antigens derived from endogenously synthesized
conjugate vaccines used to elicit antibodies that will recognize internal materials. By displaying the peptides made inside the
carbohydrate ligands expressed by bacteria. Carbohydrate moieties cell, MHC class I proteins allow circulating CD8 T cells to survey
coupled to protein carriers contain the recognition structure for host cells for expression of aberrant, mutant self proteins that
the B-cell response (the carbohydrate) and a source of CD4 may be selectively expressed in cancer or for viral protein–derived
T-cell help (the protein carrier). The requisite linkage of CD4 peptides in infected cells. Infected or cancerous host cells can
T-cell and B-cell epitopes can limit antibody responses to complex then be eliminated by the CD8 T cells.
viruses, whose protein components can become dissociated from
each other during virus replication and ensuing cell death. The Proteasome
Autophagy, or self eating, provides a major pathway for viral Proteins made within APC gain access to the host MHC class I
or self proteins to access MHC class II molecules in APCs. 17,33 following cytosolic proteolysis by the proteasome. 16,34,35 The
It is a catabolic process by which cytosolic, organelle-associated proteasome participates in protein catabolism within all cells.
and nuclear materials are delivered to endosomal and lysosomal This multimeric protein complex has a 20S catalytic core com-
compartments. Autophagy provides key metabolites that allow posed of four stacked heptameric rings, which, together, determine
cell survival under conditions of stress. It also allows access of access and the protease specificity of degradation. Proteases
self- and pathogen-derived intracellular cellular proteins into include a chymotrypsin specificity that cleaves after hydrophobic
the class II–containing compartments. Indeed, 20–30% of peptides residues, a trypsin-like activity that cleaves after basic residues
presented by class II molecules are derived from cytosolic or and a caspase-like activity that cleaves after acidic amino acid
nuclear proteins. Autophagy has also been shown to be active residues. A 19S regulator forms a lid on the proteasome and
in thymic APCs, thus broadening the array of self peptides that promotes recognition and binding of polyubiquitinated proteins,
can mediate deletion of potentially autoreactive cells during as well as unfolding and translocation of protein substrates.
development. The composition of the proteasome and its biochemical activity
Three routes by which autophagy in APCs can lead to import can vary, depending on cell type and conditions. The ubiquitously
of cellular proteins into the endosomal pathway of presentation expressed proteasome is termed the constitutive form. In response
include microautophagy, macroautophagy, and chaperone- to IFN-γ in some cell types, there is an exchange of the constitutive
mediated autophagy. All of these ultimately lead to degradation β subunits for homologous βi (for induced) subunits to create
of host proteins in the lysosome. Macroautophagy, which is the the immunoproteasome, which is expressed by many cells. The
best understood, involves formation of large, double-membrane specificity of the β 1 proteasomal subunit can lead to diminished
vesicles containing cytosolic components or cytosolic organelles cleavage of peptides with acidic residues and enrichment for
into autophagosomes. The autophagosomes fuse with endosomes peptides with hydrophobic P9 pocket residues. These changes
and lysosomes, delivering their content for degradation and fit the preferences of most class I molecules and suggest coevolu-
cellular reuse. These cytoplasmic proteins can be used as a source tion of MHC class I and the proteasome. The proteasome and
of peptides presented by class II molecules. Immunofluorescence immunoproteasome appear to primarily differ in their preferences
studies have documented delivery of autophagosomes to the for proteolytic cleavage rather than absolute specificity. Recent
lysosomal compartments that contains both conventional class studies, however, have suggested that some tumor cell recognition
II and DM proteins. epitopes are selectively destroyed by the immunoproteasome. A