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Chapter 21 T-Cell Immunity 233

to express this inhibitory receptor. Early during exhaustion, PD-1 activation even in the face of subsequent TCR stimulation by an
blockade reversed T-cell exhaustion in experimental models; however, activated APC.
other inhibitory receptors become expressed as exhaustion continues. The role of anergy in human immunology remains unclear, as
Blockade of PD-1 with these other receptors has been shown to investigators have largely used in vitro model systems and/or animal
improve T-cell responsiveness, even at later stages of exhaustion. models. However, several lines of evidence indicate that there are
Therapeutic targeting of the PD-1 axis and other key inhibitory self-antigen–reactive T cells that remain quiescent in normal human
receptors is an exciting new avenue for immunotherapy against hosts. The biochemical basis of anergy also remains incompletely
malignancies (see later) and chronic infections. understood, but intriguing models suggest that an imbalance between
the strength of Ras versus calcium signaling may be crucial. In this
paradigm, it is the activation of calcium-dependent transcription
INHIBITION OF T CELL–MEDIATED IMMUNITY factors, such as NFAT, in the absence of transcription factors
activated by Ras signaling, such as AP-1, that confers an anergic
Efficient signaling through the TCR and other cell surface molecules state. Although anergy is classically thought to persist indefinitely,
is required for initial T-cell activation. Similarly, appropriate matura- under some circumstances there is apparent plasticity, as exposure
tion of the T-cell response to generate effector and memory cells is of T cells to high concentrations of IL-2 can improve functional
critical for adequate responses to pathogens. However, because of responses in previously anergic cells. Thus the physiologic importance
the potential for activated T cells to damage host tissues, an integral of anergy in limiting endogenous T-cell activation and preventing
aspect of the immune system is also to negatively regulate T-cell autoimmunity and whether there are times when anergy must
activities. The mechanisms for inhibiting T-cell responses are critical be reversed for appropriate immune responses are areas of active
for the prevention of inappropriate activation of naive T cells at the investigation.
initiation of an immune response, for limiting the robustness of an
appropriate T-cell response as effector cell functions are developed,
and for terminating the T-cell response once an antigenic challenge Regulatory T Cells
has been met. This section discusses examples of how T-cell activation
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is modulated at each of these three critical steps of T-cell immunity. Tregs are a subset of CD4 T cells that suppress the proliferation
and cytokine production of activated T cells whose TCRs have been
Prevention of Inappropriate Initiation of engaged by peptide–MHC, even in the presence of costimulation.
Hence, as opposed to anergy, which operates in a cell-intrinsic fashion,
T-Cell Responses Tregs block responsiveness in trans, by modulating responses of other
cells. Tregs arise in two ways: “thymic” Tregs (tTregs) that acquire
Given the enormous power of immune effector cells to damage function during development in the thymus (described earlier) and
tissues, it is essential that the immune system be nonreactive (toler- “inducible” Tregs (iTregs) that are generated through the differentia-
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ant) to self. As described earlier, T-cell tolerance is achieved centrally tion of naive CD4 T cells in the periphery. Both tTregs and iTregs
through the requirement to pass selection checkpoints during thymic are characterized by expression of the key transcription factor FoxP3
development. However, negative selection in the thymus is not suf- and by surface expression of CD25, a subunit of the IL-2 receptor.
ficient to eliminate all cells with potential autoreactivity, and some As noted, there are multiple steps and checkpoints that occur
T cells bearing TCRs that may respond to self-antigens are exported during development of T cells in the thymus. After reaching the DP
from the thymus to the periphery. Mechanisms are in place to stage, T cells test their TCR for reactivity against peptide–MHC
prevent these cells from becoming active effectors as they encounter complexes presented by thymic APCs and epithelial cells. Cells
antigen. Two such mechanisms are anergy, a process by which T cells bearing TCRs with no reactivity undergo apoptosis (failed positive
limit their own responsiveness based upon engagement of particular selection) as do cells with very strong TCR reactivity (through
cell surface receptors (a cell-intrinsic path to inactivation), and the negative selection). Only cells whose TCRs have moderate affinity
action of Treg cells, which instruct potential effectors to remain for peptide–MHC continue to mature. Within this continuum of
quiescent. permitted reactivity, those cells with TCRs exhibiting the highest
affinity for peptide–MHC are induced to express FoxP3 and develop
into Tregs. In the periphery, these cells respond to TCR stimulation
Anergy by diminishing the response of “conventional” T effector cells, thus
downregulating immune responses.
One means of limiting T-cell responses against host tissues is a process iTregs act similarly to tTregs, but these cells do not leave the
of self-inactivation termed anergy. As noted earlier, T cells require thymus poised to have suppressive function. Instead, these cells arise
signaling through both the TCR and costimulatory receptors such as from naive T cells that encounter antigen in the secondary lymphoid
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CD28 to become activated (Fig. 21.5). Stimulation of the TCR alone structures. Similarly to other CD4 subsets, iTregs are induced on the
in the absence of adequate costimulation produces T cells that fail to basis of prevailing cytokine conditions and which receptor-ligand
secrete IL-2 or upregulate high-affinity receptors for this cytokine and interactions predominate during this initial antigen encounter.
hence fail to clonally expand. Cells that have been rendered anergic Regardless of whether they arise in the thymus or are induced in the
fail to respond to subsequent stimulation, even if ligands for both periphery, Tregs exert their immunosuppressive functions on a variety
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the TCR and CD28 or other costimulatory receptors are available. of immune cells, including CD4 and CD8 T cells, DCs, B cells,
This two-signal requirement ensures that only APCs activated by macrophages, and NK cells, within their microenvironment. Tregs
pathogens or other “danger signals” can initiate an immune response, mediate these immunosuppressive effects through the secretion of
because ligands for costimulatory receptors, such as CD80 and CD86, suppressor cytokines such as IL-10 and TGF-β, the consumption of
for CD28 are upregulated only in activated APCs. Thus, under local concentrations of IL-2, and the induction of apoptosis or cell
circumstances of pathogen invasion, APCs present peptide antigens cycle arrest through direct cell-to-cell contact (Fig. 21.9).
to T cells in addition to CD28 ligands. In the absence of an immune
challenge, APCs express only low levels of CD80 or CD86. If a T
cell encounters an APC that presents a stimulatory peptide–MHC Limiting T-Cell Responses After Stimulation by
complex but lacks sufficient expression of CD28 ligands, the T cell Foreign Antigen
does not become activated. In this situation, the absence of ligands
for CD28 implies that there is no “danger” and that the antigen Even when stimulated appropriately to combat an invading patho-
being recognized is derived from a self-protein. The result of such gen, it is essential to limit T-cell activation. Unchecked T-cell effec-
an encounter leaves the T cell in an anergic state, refractory to tor functions present a danger to the host through production of