Multiple Signaling Pathways Are Initiated by TCR Engagement

The events that link antigen recognition by the T-cell receptor to gene activation echo many of the themes just reviewed. The key element in the initiation of T-cell activation is the recognition by the TCR of MHC-peptide complexes on antigen-presenting cells.

As described in Chapter 9, the TCR consists of a mostly extracellular ligand-binding unit, a predominantly intracel-lular signaling unit, the CD3 complex, and the homodimer of £ (zeta) chains. Experiments with knockout mice have shown that all of these components are essential for signal transduc-tion. Two phases can be recognized in the antigen-mediated induction of T-cell responses:

■ Initiation. The engagement of MHC-peptide by the TCR leads to clustering with CD4 or CD8 coreceptors as these coreceptors bind to invariant regions of the MHC molecule (Figure 10-10). Lck, a protein tyrosine kinase associated with the cytoplasmic tails of the coreceptors, is brought close to the cytoplasmic tails of the TCR complex and phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs, described in Chapter 9). The phosphorylated tyrosines in the ITAMs of the zeta chain provide docking sites to which a protein tyrosine kinase called ZAP-70 attaches (step 2 in Figure 10-10) and becomes active. ZAP-70 then catalyzes the phosphorylation of a number of membrane-associated adaptor molecules (step 3), which act as anchor points for the recruitment of several intracellular signal transduction pathways. One set of pathways involves a form of the enzyme phospholipase C (PLC), which anchors to an adaptor molecule, is activated by phosphorylation and cleaves a membrane phospholipid to generate second messengers. Another set activates small G proteins.

■ Generation of multiple intracellular signals. Many signaling pathways are activated as a consequence of the steps that occur in the initiation phase, as shown to the right in Figure 10-10, and described below.

We shall consider several of the signaling pathways recruited by T-cell activation, but the overall process is quite complex and many of the details will not be presented here. The review articles suggested at the end of this chapter provide extensive coverage of this very active research area. Phospholipase C7 (PLCy ): PLC7 is activated by phosphoryla-tion and gains access to its substrate by binding to a membrane-associated adaptor protein (Figure 10-11a). PLC7 hydrolyzes a phospholipid component of the membrane to generate inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 causes a rapid release of Ca2+from the endoplasmic reticulum and opens Ca2+ channels in the cell membrane (Figure 10-11b). DAG activates protein kinase C, a multifunctional kinase that phosphorylates many different targets (Figure 10-11c).

Ca2+: Calcium ion is involved in an unusually broad range of processes, including vision, muscle contraction, and many others. It is an essential element in many T-cell responses, including a pathway that leads to the movement of a major transcription factor, NFAT, from the cytoplasm into the nucleus (Figure 10-11b). In the nucleus, NFAT supports the transcription of genes required for the expression of the T-cell growth-promoting cytokines IL-2, IL-4, and others. Protein kinase C (PKC): This enzyme, which affects many pathways, causes the release of an inhibitory molecule from the transcription factor NF-kB, allowing NF-kB to enter the nucleus, where it promotes the expression of genes required for T-cell activation (Figure 10-11c). NF-kB is essential for a variety of T-cell responses and provides survival signals that protect T cells from apoptotic death.

The Ras/MAP kinase pathway: Ras is a pivotal component of a signal-transduction pathway that is found in many cell types and is evolutionarily conserved across a spectrum of eukaryotes from yeasts to humans. Ras is a small G protein whose activation by GTP initiates a cascade of protein kinases known as the mitogen-activated protein kinase (MAP kinase) pathway. As shown in Figure 10-12, phosphorylation of the end product of this cascade, MAP kinase (also called

VISUALIZING CONCEPTS

Engagement of MHC-peptide initiates processes that lead to assembly of signaling complex.

VISUALIZING CONCEPTS

Engagement of MHC-peptide initiates processes that lead to assembly of signaling complex.

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ZAP-70 phosphorylates adaptor molecules that recruit components of several signaling pathways

ZAP-70 phosphorylates adaptor molecules that recruit components of several signaling pathways

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FIGURE 10-10

Overview of TCR-mediated signaling. TCR engagement by peptide-MHC complexes initiates the assembly of a signaling complex. An early step is the Lck-mediated phosphorylation of ITAMs on the zeta (Q chains of the TCR complex, creating docking sites to which the protein kinase ZAP-70 attaches and becomes activated by phosphorylation. A series of ZAP-70-catalyzed protein phosphorylations enable the generation of a variety of signals. (Abbreviations: DAG = diacylglycerol; GADS =

Grb2-like adaptor downstream of Shc; GEF = guanine nucleotide exchange factor; ITAM = immunoreceptor tyrosine-based activation motif; Itk = inducible T cell kinase; IP3 = inositol 1,4,5 triphosphate; LAT = linker of activated T cells; PIP2 = phospho-inositol biphosphage; PLC7 = phospholipase C gamma; Lck = lymphocyte kinase; SLP-76 = SH2-containing leukocyte-specific protein of 76 kDa; ZAP-70 = zeta associated protein of 70 kDa.)

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