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96 Part one Principles of Immune Response

typically involves a characteristic and large subset of the various recognition by and priming of naïve T cells can take place.
TCR Vβ families, since binding occurs outside of the TCR Resident DCs in the lymph node can also internalize antigen
peptide-binding groove. Consequently, the binding of SAgs to from the lymph drainage or from other antigen-bearing cells.
class II and TCRs can recruit as many as 20% of the total TCR In the secondary lymphoid tissue, there are limited sites in
repertoire, leading to polyclonal activation of T cells. Subsequent which the contact between circulating naïve T cells and APCs
production of proinflammatory cytokines by the activated take place. These sites are dictated by cytokines, chemokines,
T cells can lead to a profound systemic inflammatory syndrome. and a network of stromal cells that collectively controls cel-
Most notable among these is toxic shock syndrome, caused by lular trafficking and localization. In addition to the restrictions
S. aureus (toxic shock syndrome toxin [TSST]) and streptococcal imposed by APCs and T cells locating one another, naïve T
toxic shock syndrome (STSS), caused by S. pyogenes. Bacterial cells have a high threshold for activation. Active APCs require a
SAgs have also been implicated in the pathogenesis of acute high density of antigenic peptide–MHC ligands, and they must
rheumatic fever and Kawasaki disease. express accessory ligands that “costimulate” the T cells that engage
their TCR.
ANTIGEN-PRESENTING CELLS The most important type of APCs for priming CD4
Cells That Present Antigens to B Cells: Follicular and CD8 T cells are DCs that gain access to the antigen and
express costimulatory proteins that promote T-cell activation,
Dendritic Cells 14 such as B7 (CD80) and CD40. These costimulatory proteins
In absolute terms, B cells do not need another cell to present are upregulated upon encounter with pathogen-derived
antigen to them. They express antigen Ig receptors (BCRs) that pattern recognition receptors. After priming, other types of
can interact with intact proteins expressed by pathogenic organ- “professional” APCs can be recognized by T-cells, including B
isms or within protein vaccines. Physiologically, B cells typically cells and macrophages, where delivery of help for antibody
recognize their antigen as a multivalent array displayed by other responses or pathogen elimination can occur, respectively.
15
cell types. The most potent and sustained B-cell responses involve For CD4 T cells, T-cell interactions are typically limited
BCR recognition of antigen in a cellular context in conjunction to cell types that express MHC class II molecules, which are
with provision of cognate CD4 T-cell help (vide infra). However, 0only expressed on a subset of cells. B cells, macrophages, and
a polyvalent antigen, such as that displayed as highly repetitive some epithelial and endothelial cells can express class II
structures expressed on encapsulated bacteria, can elicit B-cell molecules, particularly after activation or in inflammatory
antibody responses in the absence of specific T-cell help. These cytokine milieus. In some experimental systems, more atypical
antigens are designated T-independent antigens, or “TI” antigens. APCs, such as mast cells and basophils, have been found to
Although they do not require specific CD4 T-helper (Th) cells, upregulate class II molecules and thus be targets of CD4 T cell
their responses can be enhanced by cytokines produced by other recognition. CD8 T cells can recognize a wide variety of host
cell types. cells because of the almost ubiquitous expression of MHC
Pathogen or vaccine-encoded proteins that enter the host class I molecules. Almost all nucleated cells are thus potential
and access secondary lymphoid tissue (e.g., spleen or lymph targets for CD8 T-cell recognition, a function that is critical for
nodes) are presented on the surface of specialized cell types via elimination of infected cells at many distal sites by cytolytic
high-affinity binding to cell-surface molecules, such as comple- CD8 T cells.
ment receptors or Ig Fc receptors. Antigens accessing the lymphoid
tissue can initially access and be bound via these receptors on MHC-RESTRICTED RECOGNITION OF ANTIGEN
subcapsular macrophages. Ultimately antigen accesses follicular
dendritic cells (FDCs). FDCs bind opsonized antigen via comple- TCR, the antigen-specific receptor on T cells, recognizes a physical
ment receptors (CR1 and CR2) and thus can display the intact complex between host MHC proteins and small peptide fragments
antigen directly to B cells. FDCs can maintain this antigen store derived from protein antigens (Chapter 5). The interaction
throughout the extended course of the immune responses, as between the peptide and the MHC is highly specific. Because
Ig affinity maturation takes place within the germinal center. It the genetically polymorphic regions of host MHC proteins are
is thought that binding of opsonized antigen by FDCs leads to the decisive features in the MHC that determine which peptides
recycling of the antigen complex into nondegradative, internal, are presented, this event is termed MHC-restricted presentation
endosomal compartments. This allows intermittent display of of antigen (Fig. 6.5).
the antigen at the surface as the B-cell Ig receptor repertoire
matures into highly selected B cells. These highly selected B cells Class I MHC
can differentiate into long-lived memory B cells and into plasma MHC class I proteins consist of a genetically polymorphic MHC-
cells that secrete high-affinity antibodies. encoded heavy chain and a nonpolymorphic 12-kD light chain
(β 2 M). MHC class I molecules present peptide antigens to CD8
Cells That Present Antigens to T Cells T cells, whose most common protective function is cytolysis of
T cells recognize antigen in the form of peptide fragments pathogen-infected cells or transformed tumor cells. Each molecule
presented by host MHC proteins, which are termed H-2 in the contains a series of pockets, controlled by genetically polymorphic
mouse and HLA in humans (Chapter 5). APCs mediate this amino acid residues, which allow high-affinity binding of the
process of T-cell recognition. Antigen accesses the draining lymph peptide’s side chains. The binding cleft is flanked by hydrogen
node or spleen, either directly, by drainage from a peripheral bonding residues at the periphery of the pocket so that the cleft
site or after being carried by tissue resident APCs. Peripher- is closed at its end. This peripheral closure of the binding pocket
ally distributed APCs (e.g., DCs) act as sentinels in tissue sites limits the size of peptides that can be bound and presented to
of infection (e.g., skin or lung). Here, DCs pick up and carry CD8 T cells to 8–10 amino acids (Fig. 6.6, Top). Class I molecules
pathogen-derived antigens to the draining lymph node, where are synthesized and expressed on all nucleated cells. Thus the