Immune Receptors and Signal Transduction

The idea that cells may have specific surface receptors that can be triggered by external ligands came from one of the founders of modern immunology. Paul Ehrlich, in his "side chain theory," published in 1897, conceived of antibodies on the surface of immune cells that recognize antigens and instruct the immune cell to secrete more of the same antibody. Cell surface receptors for hormones were discovered many decades later in the second half of the 20th century but well before the identification of antigen receptors on lymphocytes in the early 1980s.

Cell surface receptors serve two major functions—the induction of intracellular signaling and the adhesion of one cell to another or to the extracellular matrix. Signal transduction broadly refers to the intracellular biochemical responses of cells after the binding of ligands to specific receptors. Most but not all signaling receptors are located on the plasma membrane. Signaling initiated by these receptors typically involves an initial cytosolic phase when the receptor or proteins that interact with the receptor may be post-translationally modified. This often leads to the activation or nuclear translocation of transcription factors that are silent in resting cells, followed by a nuclear phase when transcription factors orchestrate changes in gene expression (Fig. 7-1). Some signal transduction pathways stimulate cell motility or activate granule exocytosis from the cytoplasm independent of a nuclear phase. Signal transduction can result in a number of different consequences for a cell, including acquisition of new functions, induction of differentiation, commitment to a specific lineage, protection from cell death, initiation of proliferative and growth responses, and induction of cell cycle arrest or of death by apoptosis. Antigen receptors on B and T lymphocytes are among the most sophisticated signaling machines known, and they will form a large part of the focus of this chapter.

We will initially provide a broad overview of signal transduction, followed by a discussion of signaling mediated by clonally distributed antigen receptors in lymphocytes and by structurally related immune receptors found mainly in cells of the innate immune system. When discussing antigen receptors in T and B cells, we will examine the role of coreceptors in lymphocyte activation, consider signaling through costimulatory receptors in each lymphocyte lineage, and discuss the role of inhibitory receptors in T, B, and NK cells. We will also consider different

Ligand Receptor

Cytosolic phase

Nuclear phase

Ligand Receptor

Non-receptor tyrosine kinase

Transcription factor in cytosol

Inactive downstream enzyme

Modified transcription ^C^J factor

Non-receptor tyrosine kinase

Transcription factor in cytosol

Inactive downstream enzyme

Modified transcription ^C^J factor

Nucleus

'Transcription of target gene

Nucleus

'Transcription of target gene

FIGURE 7-1 Signaling from the cell surface involves cytosolic and nuclear phases. A generic receptor that activates a nonreceptor tyrosine kinase after it binds ligand is shown. In the cytosolic signaling phase, the non-receptor kinase phosphorylates a key tyrosine residue on the cytoplasmic tail of the receptor, as a result of which the phosphotyrosine-containing receptor tail is able to recruit a downstream enzyme that is activated once it is recruited. In the cytosolic phase, this activated downstream enzyme post-translationally modifies a specific transcription factor that is located in the cytoplasm. In the nuclear phase, this modified transcription factor enters the nucleus and induces the expression of target genes that all have a binding site in the promoter or in some other regulatory region that can bind to this modified transcription factor and facilitate transcription.

FIGURE 7-1 Signaling from the cell surface involves cytosolic and nuclear phases. A generic receptor that activates a nonreceptor tyrosine kinase after it binds ligand is shown. In the cytosolic signaling phase, the non-receptor kinase phosphorylates a key tyrosine residue on the cytoplasmic tail of the receptor, as a result of which the phosphotyrosine-containing receptor tail is able to recruit a downstream enzyme that is activated once it is recruited. In the cytosolic phase, this activated downstream enzyme post-translationally modifies a specific transcription factor that is located in the cytoplasm. In the nuclear phase, this modified transcription factor enters the nucleus and induces the expression of target genes that all have a binding site in the promoter or in some other regulatory region that can bind to this modified transcription factor and facilitate transcription.

categories of cytokine receptors and signal transduction mechanisms initiated by these receptors and finally examine the major pathway that leads to the activation of NF-kB, a transcription factor of relevance to both innate and adaptive immunity.

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