TCell Receptor Complex TCRCD3

As explained in Chapter 4, membrane-bound immunoglobulin on B cells associates with another membrane protein, the Ig-a/Ig-p heterodimer, to form the B-cell antigen receptor (see Figure 4-18). Similarly, the T-cell receptor associates with CD3, forming the TCR-CD3 membrane complex. In both cases, the accessory molecule participates in signal transduction after interaction of a B or T cell with antigen; it does not influence interaction with antigen.

The first evidence suggesting that the T-cell receptor is associated with another membrane molecule came from experiments in which fluorescent antibody to the receptor was shown to cause aggregation of another membrane protein designated CD3. Later experiments by J. P. Allison and

L. Lanier using cross-linking reagents demonstrated that the two chains must be within 12 A. Subsequent experiments demonstrated not only that CD3 is closely associated with the ap heterodimer but also that its expression is required for membrane expression of ap and 78 T-cell receptors—each heterodimer forms a complex with CD3 on the T-cell membrane. Loss of the genes encoding either CD3 or the TCR chains results in loss of the entire molecular complex from the membrane.

CD3 is a complex of five invariant polypeptide chains that associate to form three dimers: a heterodimer of gamma and epsilon chains (^e), a heterodimer of delta and epsilon chains (8e), and a homodimer of two zeta chains (££) or a heterodimer of zeta and eta chains (Figure 9-9). The £ and ^ chains are encoded by the same gene, but differ in their carboxyl-terminal ends because of differences in RNA splicing of the primary transcript. About 90% of the CD3 complexes examined to date incorporate the (££) homodimer; the remainder have the heterodimer. The T-cell receptor complex can thus be envisioned as four dimers: the ap or 78 TCR heterodimer determines the ligand-binding specificity, whereas the CD3 dimers (7e, 8e, and ££ or are required for membrane expression of the T-cell receptor and for signal transduction.

Tcr Heavy Chain

Schematic diagram of the TCR-CD3 complex, which constitutes the T-cell antigen-binding receptor. The CD3 complex consists of the ££ homodimer (alternately, a £t| heterodimer) plus 7e and 8e heterodimers. The external domains of the 7, 8, and e chains of CD3 are similar to the immunoglobulin fold, which facilitates their interaction with the T-cell receptor and each other. Ionic interactions also may occur between the oppositely charged transmembrane regions in the TCR and CD3 chains. The long cytoplasmic tails of the CD3 chains contain a common sequence, the immunoreceptor tyrosine-based activation motif (ITAM), which functions in signal transduction.

FIGURE 9-9

Schematic diagram of the TCR-CD3 complex, which constitutes the T-cell antigen-binding receptor. The CD3 complex consists of the ££ homodimer (alternately, a £t| heterodimer) plus 7e and 8e heterodimers. The external domains of the 7, 8, and e chains of CD3 are similar to the immunoglobulin fold, which facilitates their interaction with the T-cell receptor and each other. Ionic interactions also may occur between the oppositely charged transmembrane regions in the TCR and CD3 chains. The long cytoplasmic tails of the CD3 chains contain a common sequence, the immunoreceptor tyrosine-based activation motif (ITAM), which functions in signal transduction.

The 7,8, and € chains of CD3 are members of the immunoglobulin superfamily, each containing an immunoglobulin-like extracellular domain followed by a transmembrane region and a cytoplasmic domain of more than 40 amino acids. The £ chain has a distinctly different structure, with a very short external region of only 9 amino acids, a transmembrane region, and a long cytoplasmic tail containing 113 amino acids. The transmembrane region of all the CD3 polypeptide chains contains a negatively charged aspartic acid residue that interacts with one or two positively charged amino acids in the transmembrane region of each TCR chain.

The cytoplasmic tails of the CD3 chains contain a motif called the immunoreceptor tyrosine-based activation motif (ITAM). ITAMs are found in a number of other receptors, including the Ig-a/Ig-p heterodimer of the B-cell receptor complex and the Fc receptors for IgE and IgG. The ITAM sites have been shown to interact with tyrosine kinases and to play an important role in signal transduction. In CD3, the 7, 8, and € chains each contain a single copy of ITAM, whereas the £ and ^ chains contain three copies (see Figure 9-9). The function of CD3 in signal transduction is described more fully in Chapter 10.

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