FIGURE 7-5 Selected members of the immune receptor family. Four selected members of the immune receptor family are depicted. Typically, immune receptors that activate immune cells have separate chains for recognition and associated chains that contain cytosolic ITAMs. Examples shown here include the B cell receptor (BCR), the T cell receptor (TCR), and the high-affinity receptor for IgE (FceRI). Inhibitory receptors in the immune system typically have ITIM motifs on the cytosolic portion of the same chain that uses its extracellular domain for ligand recognition. The inhibitory receptor shown, FcyRIIB, is found on B cells and myeloid cells.

a phospho-ITAM results in a conformational change in this kinase and its activation. The activated Syk or ZAP-70 kinase then drives immune cell activation. Some immune receptors inhibit cellular responses, and signaling chains in these receptors may contain a slightly different tyrosine-containing motif that is called an ITIM (immunoreceptor tyrosine-based inhibitory motif), which has the consensus sequence V/L/IxYxxL, where V refers to valine. Phos-phorylated ITIMs recruit tyrosine or inositol lipid phosphatases, enzymes that remove phosphate residues from phosphotyrosine moieties or from certain lipid phosphates and thus counteract ITAM-based immune receptor activation.

Members of the immune receptor family include antigen receptors on both B cells and T cells, the IgE receptor on mast cells, and activating and inhibitory Fc receptors on innate immune cells and B lymphocytes (Fig. 7-5). ITAMs are found in the cytoplasmic tails of several immune receptor complexes that are involved in signal transduction, including the Z chain and CD3 proteins of the T cell receptor (TCR) complex, Iga and IgP proteins associated with membrane Ig molecules (the antigen receptors) of B cells, and components of several Fc receptors and of the NKG2D activating receptor on natural killer (NK) cells (see Chapter 4). ITIM-containing inhibitory receptors include CD22, FcyRIIB, and several inhibitory NK cell receptors.

General Features of Antigen Receptor Signaling

Signaling downstream of the T and B cell antigen receptors is characterized by a similar sequence of events, consisting of the following.

• Receptor ligation typically involves the clustering of receptors by multivalent ligands, resulting in activation of an associated Src family kinase. Receptor ligation may also result in the unfolding of the cyto-plasmic tail of a polypeptide chain that is part of the receptor. The unfolding event (or conformational change) may allow previously hidden tyrosine residues of a cytosolic ITAM motif to become available for phosphorylation by a Src family kinase.

• The activated Src family kinase phosphorylates available tyrosines in the ITAMs of signaling proteins that are part of the receptor complex.

• The two phosphorylated tyrosines in a single ITAM are recognized by a Syk family tyrosine kinase that has tandem SH2 domains that each recognize an ITAM phosphotyrosine.

• Recruitment of the Syk family kinase to the phos-phorylated ITAM results in the activation of this tyrosine kinase and the subsequent tyrosine phosphorylation of adaptor proteins and enzymes that activate distinct signaling pathways downstream of the immune receptor.

This sequence of events is described in more detail in the context of T cell and B cell receptor signaling later in the chapter.

Alterations in the strength of TCR and B cell receptor (BCR) signaling influence the fates of lymphocytes during their development and activation. In other words, the presence of different numbers of activated signaling molecules induced by antigen-ligated receptors is interpreted differently by lymphocytes. For instance, during maturation of T cells in the thymus, weak antigen receptor signals are required for positive selection, the process that preserves useful cells by matching coreceptors to the appropriate MHC molecules, and gradations of signal strength may determine positive selection of developing T cells into the CD4 or CD8 lineage (see Chapter 8). In contrast, strong antigen receptor signals during maturation may contribute to lymphocyte death by apoptosis. The strength of TCR and BCR signaling may also differentially influence the type of immune response that is generated by a given antigen.

Antigen receptor signaling is fine-tuned and modulated by three mechanisms that are unique to this class of receptors.

• Progressive ITAM use. One of the ways in which different quantities of signal output might be generated by antigen receptors is the phosphorylation of different numbers of ITAM tyrosines after receptor engagement. The TCR complex has six signaling chains and ten ITAMs, and increasing numbers of ITAMs may be phosphorylated as the affinity of different ligands for the TCR increases. The number of ITAMs phosphory-lated may therefore provide a cytosolic interpretation of the affinity of the antigen that binds to the TCR, and antigen affinity can thus influence the nature of the cellular response at different stages of differentiation and activation. The BCR has only two ITAMs, but because this number increases when the receptor is cross-linked by multivalent antigens, the degree of cross-linking by antigens may determine the number of ITAMs that might be used and thus generate different responses to antigens of differing affinity and valency.

• Increased cellular activation by coreceptors. A core-

ceptor is a transmembrane signaling protein on a lymphocyte that can facilitate antigen receptor activation by simultaneously binding to the same antigen complex that is recognized by the antigen receptor. The coreceptor brings with it signaling enzymes linked to its cytoplasmic tail and can thereby facilitate ITAM phosphorylation and activation of the antigen receptor when antigen draws it into the vicinity of the antigen receptor. Coreceptors on T cells are the CD4 and CD8 proteins that demarcate the two functionally distinct subsets. Complement receptor type 2 (CR2/CD21) is the coreceptor on B cells.

• Modulation of signaling by inhibitory receptors. Key inhibitory receptors in T cells include CTLA-4 and PD-1, whereas important inhibitory signals in B cells are delivered through receptors such as CD22 and FcyRIIB, among others. The roles of these inhibitors are mentioned later in this chapter.

In addition, antigen receptor signals may, in some circumstances, cooperate with signals from receptors, known as costimulatory receptors, that add yet another level of control to the process of lymphocyte activation. Costimulatory receptors provide "second signals" for lymphocytes (antigen recognition provides the first signal) and ensure that immune responses are optimally triggered by infectious pathogens and substances that mimic microbes. Unlike coreceptors, costim-ulatory receptors do not recognize components of the same ligands as do antigen receptors; signal outputs downstream of costimulatory receptors are integrated with the signals derived from the antigen receptor, and these signals cooperate to fully activate lymphocytes. The prototypic costimulatory receptor is CD28 on T cells, which is activated by the costimulatory molecules B7-1 and B7-2 (CD80 and CD86), ligands induced on antigen-presenting cells (APCs) as a result of their exposure to microbes (see Chapter 9).

The T Cell Receptor Complex and T Cell Signaling

The TCR was discovered in the early 1980s, around the same time that the structure of major histocompatibility complex (MHC) molecules associated with peptides, the ligands for T cells, was being defined (see Chapter 6). A number of separate approaches were used to molecularly identify the TCR. One approach depended on the identification of genes that were expressed specifically in T cells and that also could be shown to have undergone a gene rearrangement event specifically in these cells (a characteristic feature of antigen receptor genes, described in Chapter 8). The first gene thus identified was homologous to Ig genes and proved to be a chain of the hetero-dimeric yS TCR. In another approach, clonal populations of T cells were created and monoclonal antibodies were generated against different T cell clones. Monoclonal antibodies that each recognized only a specific T cell clone were identified. These clonotype-specific antibodies identified a chain of the TCR. In yet another study, one chain of the TCR was identified serendipitously, when sequencing of a T cell-specific library of cDNAs unexpectedly revealed a novel gene with homology to immunoglobulins. We now know that the TCR is similar to antibodies, but there are important differences between these two types of antigen receptors (Table 7-1).

TABLE 7-1 Properties of Lymphocyte Antigen Receptors: T Cell Receptor and Immunoglobulins

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