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CHAPTER 12 T-Cell Activation and Tolerance 193

costimulation or when the ligand for the TCR is not of sufficient mTOR. mTOR is activated by signals that communicate abundant
affinity to initiate the full spectrum of biochemical second mes- nutrients (e.g., leucine-stimulated RAG proteins). Conversely,
sengers. Anergy is observed in T cells stimulated with metabolically mTOR is inhibited by activated AMPK, an enzyme that responds
inactivated APCs incapable of providing costimulation. Conversely, to low energy stores reflected by increased ratios of adenosine
CD28 costimulation prevents the induction of anergy. Treatment monophosphate (AMP) to adenosine triphosphate (ATP).
of cultured T cells with IL-2 can overcome the anergic state in Through mediators, such as AKT, mTOR activation functions
vitro. In addition to TCR and costimulatory signals, recent work to promote cell cycle entry and prevent transcriptional activation
has shown that environmental cues, such as nutrient and energy of the anergy factors GRAIL and CBL-b.
store availability, and the products of Tregs (described below)
also control the anergy/activation fate choice. KEY CONCEPTS
T-cell anergy can be induced by activation of the calcineurin/
NFAT pathway without concomitant increases in the RAS/ERK Immunosuppressive Drugs That Affect
pathway–dependent activating protein-1 (AP-1) transcription T-Cell Signaling
factor activity (Fig. 12.6A). Relatively unopposed NFAT activity
can be induced experimentally either by treatment with calcium • Cyclosporine and tacrolimus inhibit T-cell receptor (TCR)–generated
signals:
ionophore or by stimulation through the TCR while blocking • Anti-TCR antibodies block TCR signals
CD28 costimulation. Concurrent treatment of TCR-stimulated • CTLA-4Ig blocks CD28 signals
cells with protein synthesis inhibitors or with NFAT pathway • Rapamycin inhibits mechanistic (formerly mammalian) target of
inhibitors, such as cyclosporine, abrogates the development of rapamycin (mTOR) activation
later unresponsiveness, supporting the notion that anergy induc- • Inhibitory receptor blockade enhances antitumor function of suppressed/
tion and maintenance depend on the transcription and translation exhausted T cells
of anergy-associated factors. 41 • Anti-CTLA4 antagonist antibodies permit CD28-CD80/86
interactions
Inhibition of Ras pathway function in anergized T cells cor- • Anti-PD1/anti-PDL1 antibodies prevent suppressive interactions
relates with biochemical and gene regulatory events (see Fig. between tumor-expressed PDL1 and PD1 on tumor-infiltrating T
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12.6B). First, preferential FYN kinase–dependent activation of cells
c-CBL within anergized cells leads to recruitment of the RAF
kinase to the nucleotide exchange factor RAP1. The RAF-RAP1
association prevents RAF recruitment to RAS and thus restricts Regulation
ERK pathway activation. Second, upregulation of NFAT-dependent Subsets of T lymphocytes can enforce tolerance through active
transcription factors EGR2 and EGR3 results in transactivation regulation of autoreactive immune responses. Tregs can suppress
of proteins implicated in the restraint of T-cell activation, includ- effector functions of other immune cells of both myeloid and
ing GRAIL (gene related to anergy in lymphocytes), CBL-b, and lymphoid lineages (Chapter 18). The most extensively studied—
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ITCH. E3 ubiquitin ligase activity associated with a number and arguably the most important for tolerance induction—Treg-
of the latter factors is responsible for ubiquitin-mediated pro- sensitive immune functions are proliferation and cytokine
teolysis of TCR signal–promoting molecules, such as PKCθ and production by naïve and memory conventional T cells. Tregs
RAS-GRP. Third, posttranslational modification of the positive inhibit these processes through both cell contact–dependent
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TCR signaling mediator LAT is also observed in anergy. As and soluble molecule secretion mechanisms. By regulating the
described above, LAT is normally palmitoylated and its membrane activation and proliferation of antigen-specific effectors, Tregs
localization restricted to detergent-insoluble lipid rafts. In previ- promote tolerance to self and suppress autoimmunity in vivo.
ously anergized T cells, however, LAT palmitoylation and Identification of Tregs was initially described on the basis of
phosphorylation are both decreased. Fourth, increased expression the correlation between high CD25 expression and the potent
of members of the diacylglycerol kinase family (DGKα and suppressive activity of a subset of CD4 T cells. Most Tregs also
DGKζ) is observed in T-cell anergy. Augmented DGK expression express GITR, CD103, CTLA-4, lymphocyte activation gene-3
reflects augmented capacity for phosphorylation-dependent (LAG-3), and low levels of CD45RB. Although no single surface
conversion of DAG, the key lipid mediator upstream of RAS marker that specifies Tregs exists, CD4 T-cell expression of the
signaling, into an inert metabolite phosphatidic acid (PA). 44 transcription factor Foxp3 correlates tightly with suppressive
Cellular sensing of adequate nutrient and energy stores capacity and strongly suggests a unique differentiation pathway
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required for optimal differentiation and proliferation regulates for Tregs. The absence of Foxp3, occurring either via spontaneous
the anergy/activation T-cell fate decision. The importance of mutation (exemplified by the scurfy mouse, which develop fatal
amino acid– and energy-sensing pathways was suggested by autoimmune disease) or through targeted disruption of the gene,
observations that anergy is induced in T cells activated in the leads to the complete loss of T cells with regulatory activity.
presence of antagonists to leucine or glucose despite the presence Conditional deletion of Foxp3 in peripheral T cells results in
of robust combined antigen receptor and costimulatory pathway loss of the suppressive phenotype. Conversely, overexpression
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signaling. Several lines of evidence suggest that establishment of Foxp3 by transgenesis or retroviral methods leads to an excess
of “metabolic anergy” after integration of signaling inputs from of T cells with regulatory activity. Together, these findings suggest
antigen recognition (TCR), immune (CD28, IL-2 receptor), and that Foxp3 is both necessary and sufficient for Treg-suppressive
metabolic (e.g., GLUT1) receptors and sensors is governed by functions. The bulk of Foxp3-positive Tregs develop in the thymus.
mechanistic (formerly mammalian) target of rapamycin Dynamic Foxp3 expression and development of suppressive
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(mTOR). TCR and CD28 ligation induce T-cell anergy rather capacity can be observed in naïve CD4 T cells after exposure to
than activation when the stimuli are given in the presence of TGFβ or retinoic acid; recent work strongly suggests that inducible
rapamycin, a selective mTOR inhibitor, suggesting that optimal Treg may have nonredundant functions in suppressing chronic
T-cell activation and avoidance of anergy requires activation of inflammation. 48