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CHAPTER 12 T-Cell Activation and Tolerance 191

molecules; tumor-expressed ligands for these molecules are is required for signal initiation. The subsequent finding of a
thought to enforce a state of reduced cytolytic or cytokine- paucity of active signaling molecules located in the SMAC has
secreting functions. Monoclonal anti-PD1 and anti-PDL1 led to alternative models in which the SMAC is involved in
antagonist antibodies have recently been employed in an attempt directed cytokine secretion or in signal termination.
to reinvigorate TIL antitumor capacity. PD1/PDL1 blockade has Efficient formation of the T cell IS is heavily dependent on
sometimes resulted in dramatic tumor regressions and responses, nucleation-promoting factors, such as Wiskott-Aldrich syndrome
in responses of diverse tumors ranging from metastatic melanoma protein (WASP), which promotes reorganization of the actin
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to non–small cell lung carcinoma, to lymphoma. Other T-cell cytoskeleton. Complexes composed of TCR, active kinases, and
coinhibitors, including Lag3 and BTLA, remain under active adaptor molecules, termed microclusters, form at the immune
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investigation as potential therapeutic targets. 27 synapse within seconds following TCR engagement. TCR
A second large class of costimulatory molecules includes microclusters are dynamically regulated in space and time. Within
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members of the tumor necrosis factor receptor (TNFR) family. 2 to 3 minutes of formation, microclusters migrate along polymer-
Costimulatory TNFR family members include OX40 (CD134), ized actin from the periphery to the center of the IS, where
4-1BB (CD137), herpesvirus entry mediator (HVEM), CD30, dephosphorylation and dissociation of the components occur.
and glucocorticoid-induced TNF receptor (GITR). Cytoplasmic Sustained TCR signaling depends on constant re-formation of
domains within these type I transmembrane proteins contain microclusters containing SLP-76 and ZAP-70 at the periphery
sequences that recruit a family of adaptor molecules known as of the central zone. Costimulatory signals generated by CD28
TNF receptor–associated factors (TRAFs). Antigen receptor or the integrin very late antigen-4 (VLA-4) can alter the dynamics
costimulation functions for both CD4 and CD8 T cells have of microcluster formation and movement and enhance T-cell
been described for each member of this family. With regard to activation. The functions of either the SMAC or the microclusters
positive regulation of T-cell signaling, a well-characterized in TCR signal initiation and termination remain incompletely
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member of this group is OX40. OX40 is upregulated on activated understood.
CD4 T cells after CD3/CD28 stimulation. Trimerization of OX40
induced by engagement of APC-expressed OX40L leads to
recruitment of TRAF2, TRAF3, and TRAF5. TRAF complexes KEY CONCEPTS
control activation of a survival-enhancing NF-κB pathway. OX40 Mechanisms of Tolerance: Central and Peripheral
deficiency leads to defects in CD4 T cell proliferation, reduced
survival of effector memory T cells, and impaired formation of • Central
effective responses to secondary T-cell stimulation with antigen. • Clonal deletion/AIRE
Antibody-mediated blockade of OX40-OX40L results in reduced • Peripheral
• Immune privilege
induction of experimental autoimmune encephalitis (EAE) and • Anergy
collagen-induced arthritis. • Regulation
Knowledge of basic signaling components utilized by TCR
and costimulatory molecules has been exploited in the generation
of chimeric antigen receptors (CARs). These engineered molecules TOLERANCE
possess an antigen-specific extracellular region (often a single-
chain variable fragment), a transmembrane domain, and cytosolic Tolerance is an inherent property of the immune system that
signaling machinery from CD3 ζ-chain fused to a region from governs the ability to respond against foreign antigens (nonself)
a costimulatory molecule (e.g., CD28, OX40, 4-1BB) cytosolic without attacking the host (self). In normal hosts, tolerance
region. Cross-linking of these CARs thus may provide both signal protects against autoimmune tissue injury. The concept of
1 (TCR) and signal 2 (costimulation). T cells modified to express immune tolerance predated understanding of the cellular and
CD19-specific CARs have recently been successful in treating molecular bases for the phenomenon. Owen’s experiments in
B-cell malignancies and are being developed for use in other cattle showed that a shared blood supply during development
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malignancies. led to lifelong immune tolerance. Billingham et al. expanded
upon the concept of tolerance establishment in 1953 by showing
Spatial and Temporal Distribution of TCR that in utero inoculation with foreign tissue resulted in tolerance
Signaling Proteins to foreign skin grafts later in life. Layered and complementary
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Recent methodological advances in live cell imaging and engineer- mechanisms of immune system tolerance have developed to
ing of lipid bilayers that mimic physiological antigen-presenting calibrate immune responsiveness with maintenance of maximum
surfaces have permitted exciting insights into the temporal–spatial capacity for protective activation. The remainder of this chapter
relationships between signaling molecules. Following TCR discusses critical roles played by T cells in the establishment and
engagement, a highly organized interface termed the immunologi- maintenance of tolerance.
cal synapse (IS) forms between the T cell and the APC (Chapter Establishment of immune tolerance to self may occur either
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6). Within the IS, a number of transmembrane and cytoplasmic during T-lymphocyte development or after maturation in tissues.
proteins are coordinately polarized and form a structure called Central tolerance refers to active deletion that is induced during
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the supramolecular activation cluster (SMAC). The SMAC is development of T cells in the thymus (Chapter 8). Despite the
composed of concentric rings with a central region (cSMAC) presence of mechanisms that promote expression of a full
enriched in TCR and CD3/ζ. The more peripheral ring (pSMAC) repertoire of self-peptides (see below) in the thymus, establish-
is enriched for the integrin leukocyte function–associated ment of central tolerance alone is inadequate to prevent tissue-
antigen-1 (LFA-1). Inhibitory signaling molecules, such as the damaging autoimmune responses. In healthy vertebrate hosts,
transmembrane phosphatase CD45, are excluded from the SMAC. a small percentage of the T cells that normally develop and
These observations initially suggested that formation of the SMAC emigrate from the thymus carry autoreactive TCR. Control of