Fig. 7.25 The immune synapse provides a structure for directed secretion of T-cell cytokines. When the T-cell receptors (TcRs) on a T cell recognize peptide:mhc on an antigen-presenting cell, a process of receptor reorganization takes place on the plasma membranes of the two interacting cells. Left panel: when a cd4+ T cell recognizes its peptide:mhc ligand on a B cell, the immune synapse functions to direct T-cell-secreted cytokines onto the B-cell surface at the site of closest contact between the plasma membranes of the two cells. Right panel: confocal microscopy images of the TcR/peptide:mhc (red) and the Lfa-1/icam-1 (green) proteins 30 minutes after the initiation of signaling show a central accumulation of the TcR/peptide:mhc complexes and a peripheral ring of the Lfa-1/icam-1 complexes. These structures have been called the central supermolecular activation complex (cSmac, red) and the peripheral supermolecular activation complex (pSmac, green). The combined structure is known as the immune synapse. photograph courtesy of y. Kaizuka.
resting receptors via a low-affinity interaction with unphosphorylated ITAMs in Igα and Igβ. After the receptors have bound a multivalent antigen, which cross-links them, the receptor-associated kinases are activated and phosphorylate the tyrosine residues in the ITAMs. B cells do not express ZAP-70; instead, a closely related tyrosine kinase, Syk, containing two SH2 domains, is recruited to the phosphorylated ITAM. In contrast to ZAP-70, which requires additional Lck phosphorylation for activation, Syk is activated simply by its binding to the phosphorylated site.
For B cells, the co-receptor and co-stimulatory receptor functions are combined into one accessory receptor that is a complex of cell-surface proteins—CD19, CD21, and CD81—often referred to as the B-cell co-receptor (Fig. 7.27). As with T cells, antigen-dependent signaling from the B-cell receptor is enhanced if the B-cell co-receptor is simultaneously bound by its ligand and clusters with the antigen receptor. CD21 (also known as complement receptor 2, CR2) is a receptor for the C3dg fragment of complement. This means that antigens such as bacterial pathogens on which C3dg is bound (see Fig. 7.27) can cross-link the B-cell receptor with the CD21:CD19:CD81 complex. This induces phosphorylation of the cytoplasmic tail of CD19 by B-cell receptor-associated tyrosine kinases, which in turn leads to the binding of additional Src-family kinases, the augmentation of signaling through the B-cell receptor itself, and the recruitment of PI 3-kinase (see Section 7-4). PI 3-kinase
Fig. 7.26 Src-family kinases are associated with B-cell receptors and phosphorylate the tyrosines in ITAMs to create binding sites for Syk and Syk activation via transphosphorylation. The membrane-bound Src-family kinases fyn, Blk, and Lyn associate with the B-cell antigen receptor by binding to iTams, either (as shown in the figure) through their amino-terminal domains or by binding a single phosphorylated tyrosine through their Sh2 domains. after ligand binding and receptor clustering, the associated kinases phosphorylate tyrosines in the iTams on the cytoplasmic tails of igα and igβ. Subsequently, Syk binds to the phosphorylated iTams of the igβ chain. Because there are at least two receptor complexes in each cluster, Syk molecules become bound in close proximity and can activate each other by transphosphorylation, thus initiating further signaling.