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CHaPter 6 Overview of T-Cell Recognition 97

Activated APC
Exclude long
peptide
Co-stimulation
APC-1
MHC Class I
β 2-microglobulin
Tcell
MHC: peptide
TCR match

Activated APC
MHC Class II
β-chain
APC-2

Tcell FIG 6.6 Peptide Binding by Major Histocompatibility Complex
(MHC) Class I and II Molecules. MHC class I molecules (top)
MHC: peptide are typically “closed” at both ends. Peptides that are too long
TCR mismatch must be cleaved prior to entry into the binding site. The clefts
FIG 6.5 Major Histocompatibility Complex (MHC) Restriction of class II molecules (bottom) are “open” at the ends, and thus
Carries Out a Critical Function. Naive T cells (purple) respond permit the binding of long peptides. Both molecules interact
to cognate epitopes only when presented in association with with peptides through both hydrogen bonding residues that are
an MHC molecule on the surface of an antigen-presenting cell directed by nonpolymorphic residues in the MHC molecule and
(APC). APCs can be activated by antigen uptake, cytokines, or that are thus conserved among different complexes, and anchor-
pathogen-derived molecules, and this makes them more effective pocket interactions that typically employ polymorphic residues
at activation T cells. Experimentally observed MHC restriction in the MHC molecule and thus vary for different MHC alleles
reflects the need for the APC to bear the correct MHC that and different peptides.
matches the T cell (top). In the absence of a matched MHC,
the T cell will be unable to respond to the peptide (bottom).
KeY ConCePtS
Antigen Uptake for Presentation to CD4 T Cells
repertoire of presented peptides is widely available throughout • B cells acquire antigen through uptake by the immunoglobulin
the body for scanning by circulating CD8 T cells. receptor.
• C-type lectins expressed on the surface of many types of antigen-
Class II MHC presenting cell (APC) receptors promote the binding and internalization
of antigen by the APCs.
MHC class II proteins consist of a heterodimer of MHC-encoded, • Vaccines can be targeted to dendritic cells for CD4 T-cell priming by
genetically polymorphic α and β chains. Peptide binding is conjugation to C-type lectins and thus enhance antibody responses.
controlled by a series of 4–5 pockets into which the amino acid
side chain of peptides selectively dock. Allele-dependent amino
acid diversity within these pockets permits varied binding of
peptide fragments across individuals. Coupled with a network MHC Class II Antigen Presentation
of hydrogen-bonding residues between the main chain of the MHC class II–restricted presentation of antigen to CD4 T cells
peptide and the α helices of the MHC class II α and β chains is sensitive to inhibitors of endosomal proteolysis. Inhibitors
that stretches along the entire binding cleft, the interaction include pharmacological reagents that neutralize endosomes,
between peptide and MHC class II can be exceptionally stable. such as chloroquine or ammonium chloride, or specific protease
The class II binding cleft is open and thus can bind peptides inhibitors, such as leupeptin. These data have helped establish
ranging in length from 13 to 20 amino acids (see Fig. 6.6, Bottom). the paradigm that MHC class II molecules acquire peptides
Class II molecules are expressed on a restricted, but diverse, generated by endosomal proteolysis of internalized protein
set of cells that includes B cells, macrophages, monocytes, DCs, antigens. This process involves a number of cofactors and
and, in humans, activated T cells. Class II–bearing cells can activate checkpoints that serve to regulate MHC class II molecule traf-
CD4 T cells. CD4 Th cells promote expansion of B cells and ficking to endosomal/lysosomal compartments, acquisition of
their production of isotype-switched high-affinity antibodies. peptide, and trafficking to the cell surface. These pathways and
Interleukin-2 (IL-2)–secreting CD4 T cells facilitate CD8 T-cell mediators control the ability of class II molecules and their
expansion and generation of long-lived CD8 T memory. CD4 peptides to be recognized by CD4 T cells. Central features include
T cells can mediate protective immunity through secretion of the mechanisms that direct sorting and localization of class II
cytokines, such as interferon-γ (IFN-γ), which leads to killing molecules to the intracellular endosomal compartment(s)
of intracellular pathogens. Finally, CD4 T cells can directly kill containing antigen, proteolytic enzymes that efficiently degrade
infected host cells or class II–positive tumors via perforin- or antigen into peptides, and cofactors that promote rapid binding
granzyme-mediated cytotoxicity. of the appropriate peptides 16-19 (Fig. 6.7).