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FIGURE 7-9 Ligand-receptor pairs involved in T cell activation. A, The major surface molecules of CD4+ T cells involved in the activation of these cells (the receptors) and the molecules on APCs (the ligands) recognized by the receptors are shown. CD8+ T cells use most of the same molecules, except that the TCR recognizes peptide-class I MHC complexes, and the coreceptor is CD8, which recognizes class I MHC. Immunoreceptor tyrosine-based activation motifs (ITAMs) are the regions of signaling proteins that are phosphorylated on tyrosine residues and become docking sites for other signaling molecules. CD3 is composed of three polypeptide chains, named y, 8, and e, arranged in two pairs (ye and 8e); we show CD3 as three protein chains. B, The important properties of the major "accessory" molecules of T cells, so called because they participate in responses to antigens but are not the receptors for antigen, are summarized. CTLA-4 (CD152) is a receptor for B7 molecules that delivers inhibitory signals; its role in shutting off T cell responses is described in Chapter 9. VLA molecules are integrins involved in leukocyte binding to endothelium (see Chapter 3). APC, antigen-presenting cell; ICAM-1, intercellular adhesion molecule 1; LFA-1, leukocyte function-associated antigen 1; MHC, major histocompatibility complex; TCR, T cell receptor; VLA, very late antigen.

CD3 chains contain a negatively charged aspartic acid residue that binds to positively charged residues in the transmembrane domains of the TCR a and P chains. Each TCR complex contains one TCR aP heterodimer associated with one CD3 ye heterodimer, one CD3 Se heterodimer, and one disulfide-linked ZZ homodimer.

The cytoplasmic domains of the CD3 y, S, and e proteins range from 44 to 81 amino acid residues in length, and each of these domains contains one ITAM. The Z chain has a short extracellular region of nine amino acids, a transmembrane region containing a negatively charged aspartic acid residue (similar to the CD3 chains), and a long cytoplasmic region (113 amino acids) that contains three ITAMs. It is normally expressed as a homodimer. The Z chain is also associated with signaling receptors on lymphocytes other than T cells, such as the Fcy receptor (FcyRIII) of NK cells.

Signal Initiation by the T Cell Receptor

Ligation of the TCR by MHC-peptide ligands results in the clustering of coreceptors with the antigen receptor and phosphorylation of ITAM tyrosine residues. Phosphoryla-tion of ITAM tyrosines initiates signal transduction and the activation of downstream tyrosine kinases, which in turn phosphorylate tyrosine residues on other adaptor proteins. The subsequent steps in signal transduction are generated by the specific recruitment of key enzymes that each initiate distinct downstream signaling pathways.

It is thought that the TCR, like other immune receptors, is activated when multiple receptor molecules are brought together by binding to adjacent antigenic epitopes. However, cross-linking of the TCR poses a challenge because the induction of receptor clustering would require a high density of identical MHC-peptide complexes on APCs, and APCs generally express very few peptide-MHC complexes, perhaps as few as 100 per cell, that may be recognized by a given TCR (see Chapter 6). How, then, is the signal from the TCR initiated? It is known that antigen recognition by the TCR induces ITAM phosphorylation by active Src family kinases, but the actual mechanism of signal initiation remains to be conclusively determined. There is growing evidence that ITAMs in the TCR complex are "folded" and unavailable before the TCR recognizes antigen. Recognition of MHC-peptide complexes may induce a conformational change in the TCR, making the ITAMs associated with the linked CD3 or Z chains available for tyrosine phos-phorylation by Src family kinases. Alternatively, the activity of Src family kinases may be enhanced after receptor ligation (Fig. 7-10). The CD4 and CD8 corecep-tors (described next) greatly facilitate the activation process by bringing Lck (which is loosely associated with the tail of the coreceptor proteins) close to the CD3 and Z ITAMs (see Fig. 7-10). Eventually, a relatively stable interface is formed between the T cell and the APC, and this interface is known as the immunologic synapse (discussed later).

The Role of the CD4 and CD8 Coreceptors in T Cell Activation

CD4 and CD8 are T cell coreceptors that bind to nonpoly-morphic regions of MHC molecules and facilitate signaling by the TCR complex during T cell activation (see Fig. 7-9). These proteins are called coreceptors because they bind to MHC molecules and thus recognize a part of the same ligand (peptide-MHC complexes) that interacts with the TCR. Mature aß T cells express either CD4 or CD8, but not both. CD8 and CD4 interact with class I and class II MHC molecules, respectively, and are responsible for the class I or class II MHC restriction of these subsets of T cells (see Fig. 7-9 and Chapter 6).

CD4 and CD8 are transmembrane glycoprotein members of the Ig superfamily (Fig. 7-11). CD4 is expressed as a monomer on the surface of peripheral T cells and thymocytes and is also present on mononuclear phagocytes and some dendritic cells. It is the receptor on T cells for the envelope protein of the human immunodeficiency virus. CD4 has four extracellular Ig-like domains, a hydrophobic transmembrane region, and a highly basic cytoplasmic tail 38 amino acids long. The two N-terminal Ig-like domains of the CD4 protein bind to the nonpoly-morphic ß2 domain of the class II MHC molecule.

Most CD8 molecules exist as disulfide-linked heterodi-mers composed of two related chains called CD8a and CD8ß (see Fig. 7-11). Both the a chain and the ß chain have a single extracellular Ig domain, a hydrophobic transmembrane region, and a highly basic cytoplasmic tail about 25 amino acids long. The Ig domain of CD8 binds to the nonpolymorphic a3 domain of class I MHC molecules. Some T cells express CD8 aa homodimers, but this different form appears to function like the more common CD8 aß heterodimers. These homodimers are also present on a subset of murine dendritic cells (see Chapter 6).

The cytoplasmic tails of both CD4 and CD8 bind the Src family kinase Lck. The ability of these coreceptors to bind to MHC molecules helps these proteins to be drawn adjacent to the TCR that contacts the same MHC-peptide complex on the APC. As a result, on the cytosolic face of the membrane, Lck is drawn very close to the ITAMs in CD3 and Z proteins and phosphorylates the ITAMs, thus facilitating the subsequent recruitment and activation of the kinase ZAP-70.

Activation of Tyrosine Kinases and a Lipid Kinase During T Cell Activation

Phosphorylation of residues in proteins and lipids plays a central role in the transduction of signals from the TCR complex and coreceptors. Within seconds of TCR ligation, many of the tyrosine residues within the ITAMs of the CD3 and Z chains become phosphorylated (see Fig.7-10). In addition to coreceptor-associated Lck, another Src family kinase that is found in physical association with the TCR complex is CD3-associated Fyn, and it may play a role similar to that of Lck. Knockout mice lacking Lck show some defects in T cell development, and double knockout mice lacking both Lck and Fyn show even more severe defects.

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