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C H A P T E R 21

T-CELL IMMUNITY

Shannon A. Carty, Matthew J. Riese, and Gary A. Koretzky

INTRODUCTION pathogens, whereas CD8 T cells function largely by directly lysing
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host cells that have become infected with an intracellular organism.
Thymus-derived (T) lymphocytes play an essential role in the It is therefore critical for antigens derived from extracellular sources
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immune response to pathogens and against host cells that have to stimulate CD4 T cells and for antigens derived from within the
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undergone malignant transformation. T cells are critical regulators of cell to stimulate CD8 T cells. Whether a particular antigenic peptide
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other arms of the immune system via soluble mediators they produce activates a CD4 versus a CD8 T cell is determined by which MHC
and through direct interactions between ligands on the T-cell surface proteins present the peptide to the TCR.
and receptors on other immune cells. This chapter first reviews T-cell Class II MHC proteins are found on cells of the innate immune
activation after engagement by specific antigens and describes how system known as “professional” antigen-presenting cells (APCs)
signals delivered by the antigen receptors shape the repertoire of as well as B cells and the thymic epithelium. Professional APCs
mature T cells in secondary lymphoid organs. We then discuss how include dendritic cells (DCs) and various tissue macrophages, which
different populations of mature T cells exert their effector functions. engulf extracellular organisms (often after these are coated with host
Because homeostasis of the immune system requires not only that antibodies), host cells that have undergone apoptosis (programmed
T cells become activated under appropriate conditions but also that cell death), and cellular debris through an endocytic pathway that
their activity be curtailed once the pathogenic challenge has been met, brings the ingested material into contact with degradative enzymes.
we describe several means by which T-cell activation is terminated. The peptides that are formed in these reactions are bound to the
Finally, we review recent therapeutic advances that make use of our MHC class II proteins for presentation to T cells. The MHC class
understanding of the molecular basis for T-cell activation. II complex is a dimer consisting of a single α chain and a single β
chain. Both α and β contribute to peptide binding and interaction
with the TCR. As they are being synthesized within the cell, MHC
T-CELL ACTIVATION class II complexes bind invariant chain (Ii), a protein that directs
the newly formed MHC proteins into an acidic vesicle. During this
T-cell activation begins when the T cell encounters a specific antigen trafficking event, a portion of the Ii occupies the peptide-binding
that engages and then initiates signal transduction through the T-cell site. Once the MHC class II protein reaches the acidic vesicle, Ii
antigen receptor (TCR). Unlike B cells that respond to soluble anti- is proteolyzed by cathepsin S, leaving behind a small fragment that
gens, T cells are stimulated by small peptides presented on the surface remains lodged within the peptide-binding cleft of the MHC class II
of other cells. These peptides are incorporated into the binding complex. This fragment is termed the class II–associated invariant chain
groove of proteins of the major histocompatibility complex (MHC, peptide (CLIP). The MHC class II–containing vesicles then fuse with
known in humans as human leukocyte antigen [HLA] complexes) other vesicles containing the peptide fragments from the endocytosed
through a process called antigen presentation. Thus the ligand for the particles. There, CLIP is replaced with a peptide, thus stabilizing the
TCR is a peptide surface that is generated from both amino acids MHC class II complex and allowing it to be transported to the cell
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in the antigenic peptide and residues found in the MHC molecules surface, where it interacts with CD4 T cells (Fig. 21.1).
themselves. Engagement of peptide–MHC complexes by the TCR All cells of the body are at risk of being infected with intracellular
induces a series of intracellular biochemical events that culminate pathogens or becoming transformed. Because protection against such
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in T-cell activation. Although T cells make use of many of the same challenges requires a CD8 T-cell response, all nucleated cells in the
biochemical pathways used by other cells for activation, there are a body express class I MHC, the protein complex that presents antigen
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number of molecules unique to immune cells that are critical for to CD8 T cells. Like class II MHC, class I MHC is a protein
T-cell activation. This section discusses TCR signal transduction, dimer. However, in contrast to class II, only the α chain of class I
focusing on immune cell-specific molecular events. MHC is variable. This α chain is associated with β 2 microglobulin,
which stabilizes the complex but plays no direct role in antigen
Antigen Presentation: Creating the Ligand for the presentation. During its assembly in the endoplasmic reticulum (ER),
the MHC class I complex comes into contact with peptides derived
T-Cell Receptor from proteins being translated in the cell. During protein synthesis,
small amounts of protein are modified by ubiquitinylation. This
Invading pathogenic bacteria and viruses use different strategies to serves as a targeting sequence, directing the modified protein to
survive within infected hosts. Many bacteria, such as the pathogens the proteasome, where it is degraded into small peptide fragments.
Staphylococcus, Streptococcus, and various enteric Gram-negative These fragments are transported back into the ER by the transporters
bacilli, survive in the extracellular milieu, whereas viruses and other associated with antigen processing (TAP-1 and TAP-2), where they
bacteria, such as Listeria, survive inside host cells. Successful elimina- become available for binding to the newly synthesized MHC class I
tion of pathogens in each of these locations requires distinct responses complexes. Peptide association completes the folding and assembly
from the host. T cells play a central role in the control of extracellular of MHC class I, which is then transported to the cell surface, where
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and intracellular pathogens; however, the subset of T cells differs for it can be recognized by CD8 T cells.
each type of pathogen, with T cells expressing the cell surface marker T cells can respond to antigenic peptides only if these peptides
CD4 most important for the response against extracellular pathogens fit into the binding pocket of either MHC class I or MHC class II.
and those expressing the CD8 marker essential for control of intracel- Although a large number of peptides are able to bind to a specific
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lular organisms. Stimulated CD4 T cells act on other cells of the MHC complex, the diversity of antigen presentation is enhanced
immune system by producing cytokines, soluble mediators that elicit through expression of three different MHC class I alleles (in humans,
a variety of cellular responses important for clearance of extracellular HLA A, B, and C) and class II alleles (in humans, HLA DR, DP,

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