Cd4

brane monomer consisting of four extracellular Ig domains, a transmembrane domain, and a cytoplasmic tail. The CD8 protein is either a disulfide-linked aP integral membrane heterodimer or a disulfide linked aa homodimer (not shown). Each chain has a single extracellular Ig domain. The cytoplasmic portions of both CD4 and CD8 can associate with Lck (not shown).

brane monomer consisting of four extracellular Ig domains, a transmembrane domain, and a cytoplasmic tail. The CD8 protein is either a disulfide-linked aP integral membrane heterodimer or a disulfide linked aa homodimer (not shown). Each chain has a single extracellular Ig domain. The cytoplasmic portions of both CD4 and CD8 can associate with Lck (not shown).

FIGURE 7-12 Role of PI3-kinase in T cell responses. Membrane PIP3, generated by PI3-kinase (PI3K), activates PDK1, which phos-phorylates and activates the Akt kinase. This enzyme phosphorylates downstream targets that are involved in cell survival.

Cell survival

FIGURE 7-12 Role of PI3-kinase in T cell responses. Membrane PIP3, generated by PI3-kinase (PI3K), activates PDK1, which phos-phorylates and activates the Akt kinase. This enzyme phosphorylates downstream targets that are involved in cell survival.

The tyrosine-phosphorylated ITAMs in the Z chain become "docking sites" for the Syk family tyrosine kinase called ZAP-70 (Z-associated protein of 70 kD). ZAP-70 contains two SH2 domains that can bind to ITAM phos-photyrosines. Each ITAM has two tyrosine residues, and both of these must be phosphorylated to provide a docking site for one ZAP-70 molecule. The bound ZAP-70 becomes a substrate for the adjacent Lck, which phosphorylates specific tyrosine residues of ZAP-70. As a result, ZAP-70 acquires its own tyrosine kinase activity and is then able to phosphorylate a number of other cytoplasmic signaling molecules. A critical threshold of ZAP-70 activity may be needed before downstream signaling events will proceed, and this threshold is achieved by the recruitment of multiple ZAP-70 molecules to the phosphorylated ITAMs on the Z chains and on CD3 tails.

Another signaling pathway in T cells involves the activation of PI3-kinase, which phosphorylates a specific membrane-associated inositol lipid (Fig. 7-12). This enzyme is recruited to the TCR complex and associated adaptor proteins and generates phosphatidylinositol tri-sphosphate (PIP3) from membrane phosphatidylinositol bisphosphate (PIP2) on the inner leaflet of the plasma membrane. Certain signaling proteins in the cytosol have specialized PH domains that have an affinity for PIP3, and as a result, PH domain-containing proteins can bind to the inside of the cell membrane only when PIP3 is generated. Examples of PH domain-containing proteins include kinases such as Itk in T cells and Btk in B cells. Another important PIP3-dependent kinase is PDK1, which is required for the phosphorylation and activation of an important downstream kinase called Akt. Activated Akt phosphorylates crucial targets and contributes to cell survival in a number of ways. Phosphorylation by Akt leads to the inactivation of two proapoptotic members of the Bcl-2 family, BAD and BAX. Akt also inactivates a

Forkhead family transcription factor that induces the expression of Fas ligand, and this kinase also targets caspase-9 for degradation.

Recruitment and Modification of Adaptor Proteins

Activated ZAP-70 phosphorylates several adaptor proteins that are able to bind signaling molecules (see Fig. 7-10). A key early event in T cell activation is the ZAP-70-mediated tyrosine phosphorylation of adaptor proteins such as SLP-76 and LAT. Phosphorylated LAT directly binds PLCy1, a key enzyme in T cell activation (discussed later), and coordinates the recruitment of several other adaptor proteins, including SLP-76, GADS, and Grb-2, to the cluster of TCR and TCR-associated proteins, sometimes referred to as the signalosome. Thus, LAT serves to bring a variety of downstream components of TCR signaling pathways close to their upstream activators. Because the function of many of these adaptors depends on their tyrosine phosphorylation by active ZAP-70, only antigen recognition (the physiologic stimulus for ZAP-70 activation) triggers the signal transduction pathways that lead to functional T cell responses.

Formation of the Immunologic Synapse

When the TCR complex recognizes MHC-associated pep-tides on an APC, several T cell surface proteins and intra-cellular signaling molecules are rapidly mobilized to the site of Tcell-APCcontact (Fig. 7-13). This region of physical contact between the T cell and the APC forms a bull's-eye-like structure that is called an immunologic synapse or a supramolecular activation cluster (SMAC). The T cell molecules that are rapidly mobilized to the center of the synapse include the TCR complex (the TCR, CD3, and Z chains), CD4 or CD8 coreceptors, receptors for

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