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Chapter 21 T-Cell Immunity 235

with T-cell activation. Moreover, CTLA-4 binds CD80 and CD86 signaling through JAKs, resulting in the nuclear translocation of
with much higher affinity than CD28, thus sequestering these key STAT proteins and the implementation of a transcriptional program
ligands away from CD28. The importance of CTLA-4 in controlling that results in decreased expression of inflammatory cytokines and in
immune reactions was highlighted in the study of CTLA-4-deficient antagonism of crucial signaling molecules.
mice, which were found to die as a result of autoimmune disease at IL-10 exerts broad changes within the immune system. In mono-
3 to 4 weeks of age. Targeting CTLA-4 with blocking antibodies to cytes, IL-10 decreases the production of inflammatory mediators and
augment T-cell responses is a new therapeutic strategy for human antigen presentation. In T cells, the effects of IL-10 are generally
cancer treatment (see later). Conversely, providing soluble CTLA-4 inhibitory, resulting in decreased capacity for proliferation and a
to patients with autoimmunity has been shown to be effective at decreased capacity to secrete cytokines. These effects vary by T-cell
blocking T-cell activation, presumably by acting as a competitive subtype, however, as IL-17 secretion by Th17 cells is not impaired in
antagonist and interfering with the ability of CD28 to bind to its the presence of IL-10. As in other proteins important in the negative
ligands, resulting in an anergizing signal to T cells. regulation of T cells, IL10 germline deletion often results in fatal
autoimmunity, in this case a gastrointestinal disease resulting from
the inability to control inflammation caused by commensal bacteria.
E3 Ubiquitin Ligases TGF-β is a pleiotropic inhibitor that acts as a potent immuno-
suppressor. As noted, TGF-β is important both in its capacity to
TCR signaling is also limited through the targeted destruction of upregulate the transcription factor FoxP3, required for the generation
proteins required for TCR signal transduction. E3 ubiquitin ligases of Tregs, and in inducing more global changes that favor immu-
are a class of proteins that target intracellular proteins for degrada- nosuppression. TGF-β binds its cell surface receptor complex and
tion by the proteasome, the large multisubunit cytosolic complex subsequently induces the phosphorylation, activation, and nuclear
essential for protein turnover. In T cells, several E3 ubiquitin ligases transport of intracellular Smad proteins. Effector Smad proteins exert
target components of TCR signal transduction for degradation after their effects by directly coordinating transcriptional programs that
TCR activation. These include Casitas b-lineage lymphoma-b (Cbl- inhibit immune responsiveness. Like IL-10, TGF-β acts on numerous
b), c-Cbl, and Itch, among many others. As with other negative cell types. It has been shown to inhibit the differentiation of effector
modulators of TCR signaling, genetic deletion of E3 ubiquitin ligases, Th cells; induce the conversion of naive T cells into Tregs; suppress
either alone or in combination, results in dysregulation of immune the proliferation and production of IL-2 by T cells; and inhibit the
function or the development of frank autoimmune disease in mice. activity of macrophages, DCs, and APCs. Mice lacking TGF-β1
The targeted degradation of crucial signaling modulators after T-cell develop autoimmune-mediated multiorgan failure and die shortly
activation thus serves as an additional physiologic mechanism to limit after birth, underscoring the important role that this molecule plays
T-cell responses. in attenuating immune reactions.

Diacylglycerol Kinases Terminating Immune Responses After
Pathogen Clearance
Intrinsic cellular components limit T-cell activity through degra-
dation of second messengers of T-cell signal transduction, such The simplest way in which T-cell responses end following clearance
as metabolism of diacylglycerol (DAG) by diacylglycerol kinases of a pathogenic challenge is by the removal of antigen, which limits
(DGKs). As described earlier, engagement of the TCR results in the perpetuation of T-cell activation and abrogates the recruitment
the activation and recruitment of PLCγ1 that cleaves PIP 2 into the of new effector cells. Effector functions of those T cells that were
second messengers DAG and IP 3 . DAG levels are regulated in T cells stimulated to respond to the pathogen challenge also diminish
through the activity of DGKs that metabolize DAG to terminate as the inhibitory mechanisms described earlier exert their effects.
its ability to transduce signals. Two DGK isoforms, DGK-α and However, homeostasis of the immune system also requires that the
DGK-ζ, are important for limiting TCR signaling, as deletion of majority of those T cells that emerged from the clonal expansion of
either in mice results in enhanced proliferation and cytokine produc- antigen-stimulated cells (at its peak representing several percent of the
tion after TCR stimulation. Moreover, deletion of DGK-α leads to hosts’ T-cell pool) be eliminated, retaining only a small population
impaired induction of T-cell anergy. Mice deficient in either isoform of memory T cells responsive to the inciting antigens. Elimination
of DGK do not develop overt autoimmune disease, likely because of the expanded population occurs through activation-induced cell
of some biochemical redundancy between the isoforms, and, in the death (AICD).
case of DGK-z, enhanced numbers of tTregs. However, enhanced AICD is initiated when CD95 (also called Fas), a T-cell surface
functional responses to viral infection and tumors have been reported receptor present on the activated effector cells, is engaged by its ligand
in DGK-deficient T cells, defining an important role for DGKs in (CD95 ligand), expressed on multiple immune cells, including the
limiting immune responses. activated cells themselves. CD95 is a member of the TNF family of
receptors and, when stimulated, recruits the adapter molecule Fas-
Limitation of T-Cell Activity From activating via death domain (FADD). FADD creates a multimolecular
complex that triggers the activation of several intracellular caspases
Cell-Extrinsic Components that induce DNA damage and apoptosis of the effector T cell. During
T-cell activation, both CD95 and CD95 ligand are upregulated on
Extrinsic factors also help limit the function and activation state of the surface of the cell, and all of the machinery is present to initiate
T cells. The predominant influences of T cells in this respect are AICD. Hence the default pathway for activated T cells is apoptosis,
inhibitory cytokines that bind cell surface receptors and influence an event that is blocked when T cells are appropriately stimulated
transcriptional changes that favor decreased activation. Two cytokines to respond to antigen. Once antigen is cleared and the stimulatory
that serve as a paradigm for understanding cytokine-mediated inhibi- events cease, AICD takes over, reducing the expanded population of
tion of T cells are IL-10 and TGF-β. cells (Fig. 21.11).
IL-10 is a major negative regulator of immune effector function. Experiments of nature have taught us much about the biology
Its central role is underscored by the fact that pathogenic viruses, and importance of both CD95 and CD95 ligand. Loss of these
such as cytomegalovirus and Epstein-Barr virus, use homologs of proteins as well as components of their signaling machinery results
IL-10 to subvert immunologic activity and create environments more in the human disease autoimmune lymphoproliferative syndrome
favorable for viral spread and replication. IL-10 is produced by both (ALPS). ALPS is characterized by massive enlargement of lymphoid
innate and adaptive immune cells in response to activation. As with organs, autoimmune cytopenias, and an increased risk of hematologic
other cytokines, binding of IL-10 to the IL-10 receptor induces malignancy.