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Chapter 21 T-Cell Immunity 231

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been approved or are under active clinical investigation for treating lymph nodes, where they encounter recirculating naive CD8 cells.
these disorders. TCR engagement of foreign peptide–MHC class I complexes triggers
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activation of the CD8 T cells and initiates CTL differentiation. As
part of its activation program, the CTL changes its expression of
Tfh Cells integrins and chemokine receptors so that it can leave the circulation
and enter the tissues, looking for host cells displaying the same
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In addition to Th1, Th2, and Th17 subsets, naive CD4 cells develop antigen that induced CTL activation by the APC in the lymph node.
other functions dependent on the cytokines produced. Examples Once an appropriate target cell is identified in the tissues, the CTL
include recently described Th9, Th22, and Tfh cells. This latter is again stimulated through its TCR, this time by the peptide–MHC
subset enhances the humoral immune response by providing help to class I combination on the target cells. A structure similar to the
B cells during germinal center reactions. Tfh cells express high levels IS forms between the CTL and the target cell. The CTL contains
of CXCR5, the receptor for the chemokine CXCL13. The expression specialized granules that are transported to the contact site between
of CXCR5 permits differentiating Tfh cells to migrate from the the CTL and target. These granules are modified lysosomes that
T-cell zone to the CXCL13-rich B cell follicle, thereby allowing Tfh contain effector proteins, including perforin, granzymes, and granu-
cells to interact with B cells and exert their function. In addition to lysin. Perforin facilitates the entry of the granzymes into the cytosol
CXCR5 expression, other signals, such as TCR signal strength and of the target cell. The granzyme family, consisting of granzyme
costimulatory molecules, are important for Tfh differentiation. A A, granzyme B, granzyme H, granzyme K, and granzyme M, are
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study using adoptive transfer of naive CD4 cells expressing high- proteases that degrade host cell proteins. Granzyme B is the best-
and low-affinity transgenic TCRs demonstrated that high-affinity studied family member and is known to cleave caspase 3, activating
TCR interactions preferentially developed into the Tfh subset. Tfh a proteolytic cascade leading to DNA degradation and apoptosis of
cells have higher expression of multiple costimulatory molecules, the target cell (Fig. 21.8). Granzyme B also promotes cell death in
including CD40L, ICOS, and OX40, than other T helper subsets. a caspase-independent manner through cleavage of the proapoptotic
Because costimulatory molecules enhance B cell differentiation, the protein Bid, promoting its migration to and disruption of the outer
higher expression of these molecules on Tfh cells is hypothesized mitochondrial membrane, resulting in the release of cytochrome c.
to positively correlate with the enhanced ability to facilitate B cell CTLs also produce cytokines, including IFN-γ, TNF-α, and IL-2.
antibody production. It appears that the expression of costimulatory IFN-γ acts to inhibit viral replication in the affected tissues and also
molecules on Tfh cells is important not only for their function but induces increased class I MHC expression, thus improving the ability
also for their development and/or maintenance, because both mice of cells to stimulate the TCR on CTLs. IFN-γ synergizes with TNF-α
and humans deficient in ICOS have fewer Tfh cells with reduced for macrophage activation.
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germinal center formation. The transcription factors important for CD8 T-cell effector
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Similarly to other CD4 helper subsets, Tfh programming depends differentiation include two members of the T-box family, T-bet
on a signature transcription factor, in this case B-cell lymphoma 6 and Eomesodermin (Eomes). Initially identified as the master Th1-
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protein (Bcl-6). In Tfh cells, Bcl-6 acts as a transcriptional repressor. determining transcription factor in CD4 cells, T-bet also plays an
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Studies employing complementary methods of T cell–specific Bcl-6 essential role in CD8 effector cell differentiation. Recent work has
deficiency and overexpression demonstrated that Bcl-6 expression in shown that T-bet expression is highest in short-lived effector cells and
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T cells is both necessary and sufficient for Tfh differentiation in vivo. lower in CD8 T cells destined to become memory cells (see later),
suggesting that a gradient of T-bet expression controls the balance
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between different CD8 effector fates. Eomes cooperates with T-bet
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CD4 Th Plasticity in CTL function, and cells deficient in both factors are unable to
generate CTLs in response to viral infection.
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Although CD4 T helper differentiation was classically thought to
be a model of lineage specification and differentiation, it is clear that
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there is more plasticity in the CD4 Th subsets than was originally MATURATION OF T CELL–MEDIATED IMMUNITY
appreciated. Traditionally, Th subsets are associated with a signature
cytokine(s) and transcription factor. However, recent data demon- T-Cell Memory
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strate CD4 Th cells can express more than one cytokine, particularly
in vivo, and even the “master regulators” can be coexpressed in The activation of naive T cells does not complete their maturation
the same cell. The mechanisms that underlie this plasticity and its process; instead, it is the starting point for the changes that result
functional relevance are areas of active investigation. in T cell–mediated immunity. At the initiation of an infection,
individual antigen-specific T cells become activated and expand
robustly to combat the pathogen. As the pathogen is eradicated, the
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CD8 Cytotoxic T Cells large population of activated T cells must contract dramatically to
ensure homeostasis of the immune system. However, a discrete but
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The principal function of CD8 cytotoxic T cells (CTLs) is to kill host relatively small population of antigen-specific T cells persists. These
cells that have been infected with pathogens or that have undergone long-lived T cells have properties distinct from naive or activated T
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deleterious changes, such as malignant transformation. Like CD4 cells, including self-renewal through homeostatic proliferation and
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cells, naive CD8 cells initially encounter peptide antigen and MHC the ability to rapidly proliferate and regain effector function upon
on the surface of APCs in the secondary lymphoid organs. However, reexposure to antigen. These are the cardinal features of cell-mediated
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unlike CD4 cells that are stimulated by class II MHC alleles on the immunologic memory.
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APCs, CD8 cells are engaged by class I MHC plus peptide. For Immunologic memory refers to the observation that after an initial
many years it remained unclear how APCs, which acquire peptide exposure and mounting of an effective immune response to a patho-
antigens largely by engulfing materials generated outside the cell, are gen, subsequent interactions with that pathogen elicit rapid and
able to present MHC class I–restricted peptides, which typically are robust T-cell activation, with more efficient clearance of the pathogen.
generated within the cell (see earlier). This mystery was solved with Memory is the foundation of vaccination because immunization with
the description of “cross-presentation,” a mechanism by which APCs pathogen-specific antigens induces a memory response so that first
present engulfed antigens on both class I and class II alleles. Thus, exposure of the host to the intact pathogen results in a rapid, effective
tissue-resident phagocytic cells ingest virally infected or malignantly response, thus abrogating signs and symptoms of the infection.
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transformed host cells, degrade the ingested material, and present Within days of infection, subsets of activated effector CD8
the peptide antigens in the binding grooves of both class I and class T cells can be identified with different cell fates: those that are
II MHC alleles. These activated phagocytic cells then migrate to the terminally differentiated and those that have the potential to develop