Page 203 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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T-Cell Activation and Tolerance

Erik J. Peterson, Jonathan S. Maltzman

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Activation of T lymphocytes during an immune response triggers capability. Specificity of the TCR for antigen resides exclusively
a series of programmed gene regulation, proliferation, differentia- within the highly polymorphic, clonotypic, ligand-binding α/β
tion, and effector functions. These T-cell functions coordinate or γ/δ heterodimers. Although many of the biochemical events
with other leukocytes to permit the immune system to react leading to α/β and γ/δ T-cell activation are similar, α/β T cells
against foreign antigens without initiating self-reactivity or exhibit a broader spectrum of antigen reactivity and are thought
autoimmunity. Each of these functions is fully dependent on to participate in a wider range of specific immune responses.
environmental cues that are recognized by cell surface receptors This chapter focuses on α/β T cells.
and are then translated through biochemical alterations within The α/β TCR specifically recognizes short peptide ligands
the cell. This chapter discusses signal transduction through one bound to major histocompatibility complex (MHC) antigens
of the most studied of these receptors, the antigen-specific T-cell (Chapter 5) on the surface of antigen-presenting cells (APCs)
receptor (TCR) complex. It addresses the mechanisms whereby (Chapter 6). Coreceptor molecules expressed on subsets of α/β
signals propagated through the TCR combine with those from T cells determine whether the TCR recognizes class I or class II
costimulatory receptors to produce either productive activation MHC. CD4 T cells are stimulated by processed exogenous antigen
or immune tolerance. It also discusses how abnormal TCR signal- presented by class II MHC molecules on the surface of professional
ing, and imbalanced signaling through costimulatory or coinhibi- APCs. CD8 T cells respond to peptides synthesized by APCs and
tor molecules, can contribute to T-cell dysfunction and disease presented by class I molecules. CD4 and CD8 associate with
(Table 12.1). Targeting these molecular pathways has resulted MHC class II and class I molecules, respectively, to stabilize the
in several clinically relevant drugs currently used to treat autoim- tripartite interaction between the TCR, antigen, and MHC, which
munity, transplant rejection, and cancer. increases the effectiveness of TCR engagement.
Although the α/β chains of the TCR contain all of the informa-
CLINICAL RELEVANCE tion necessary for antigen/MHC binding, these proteins are
not sufficient to initiate the intracellular biochemical events
• Dysfunction or deficiency of T-cell signaling proteins (induced or that signal antigen recognition. Instead, signal transduction is
spontaneous) has been causally linked to several disease states in accomplished by noncovalently associated CD3 and TCRζ
animal or human models. Molecules wherein mutations may lead to polypeptides, which include several pairs of transmembrane
immune deficiency or dysregulation include: hetero- or homodimers (Fig. 12.1). Each CD3 and ζ chain derives
• CD45 signaling capacity from the presence of one or more cytoplasmic
• LCK
• ZAP-70 regions known as immunoreceptor tyrosine-based activation motifs
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• SLP-76 (ITAMs).
• LAT
• IL-2R γ chain
• Mst1 KEY CONCEPTS
• Molecules wherein mutations may lead to lymphocyte hyper- Protein Tyrosine Kinase Activation
proliferation include:
• CTLA-4 T-cell receptor engagement activates several families of protein tyrosine
• SHP-1 kinases, which are required for propagation of second messenger-instigated
• CD95/CD95 ligand intracellular signaling:
• SAP • Src family: LCK, FYN
• CBL/CBL-b • Syk family: ZAP-70
• ZAP-70 • Tec family: ITK, RLK
• LYP
• DGK
Activation of Protein Tyrosine Kinases by the TCR and
THE T-CELL ANTIGEN RECEPTOR COMPLEX the Role of the ITAMs
Among the earliest of the biochemical events following engage-
The TCR complex consists of a ligand-binding TCR α/β or γ/δ ment of the TCR is the activation of LCK and FYN, two members
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heterodimer (Chapter 4) in association with the CD3/ζ chain of the SRC family of protein tyrosine kinases (PTKs). Along
complex, which provides transmembrane signal transduction with all SRC family PTKs, LCK and FYN share features critical
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