The antigen receptors on the surface of lymphocytes are multiprotein complexes in which the antigen-binding chains interact with additional proteins that are responsible for signaling from the receptor. These protein chains carry tyrosine-containing signaling motifs known as ITAMs. Signaling chains containing ITAM motifs are widely used by activating receptors in many immune cell types in addition to lymphocytes. In lymphocytes, activation of the receptors by antigen results in a series of biochemical events that are broadly outlined in Fig. 7.28. This signaling cascade is initiated by the phosphorylation of the ITAMs by Src-family kinases. The phosphorylated ITAM then recruits another tyrosine kinase, ZAP-70 in T cells and Syk in B cells. Activation of ZAP-70 or Syk results in the phosphorylation of scaffolds called LAT and SLP-76 in T cells, and SLP-65 in B cells, and in the activation of PI 3-kinase. Multiple signaling proteins are recruited and activated by these phosphorylated scaffolds, including phospholipase C-γ, ADAP, and Vav, whereas Akt is recruited and activated by the action of PI 3-kinase generating PIP3 at the plasma membrane. PLC-γ generates inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 has an important role in inducing changes in intracellular calcium concentrations, and DAG is involved in activating protein kinase C-θ and the small G protein Ras. In T cells, these pathways ultimately result in the activation of three transcription factors, namely, AP-1, NFAT, and NFκB; together, these transcription factors induce transcription of the cytokine IL-2, which is essential for the proliferation and further differentiation of the activated lymphocyte. In addition to transcription factor activation, antigen receptor signaling in both T cells and B cells leads to enhanced cell survival, metabolic activity, adhesiveness, and cytoskeletal reorganization. Signaling by antigen receptors is facilitated by co-receptors that become engaged as a result of receptor–antigen binding. These co-receptors are the MHC-binding CD4 and CD8 transmembrane proteins in T cells and the complement-binding B-cell co-receptor complex containing CD19 in B cells.
Co-stimulatory and inhibitory receptors modulate antigen receptor signaling in T and B lymphocytes.
Signals initiated by the T-cell and B-cell antigen receptors are essential for lymphocyte activation, and determine the specificity of the adaptive immune response that is initiated. However, signaling from the antigen receptor is not on its own sufficient to activate a naive T cell or B cell. These naive lymphocytes require additional signals to achieve full activation. Receptors on T cells and B cells that can provide this necessary second signal are called costimulatory receptors, and are members of either the CD28 family of proteins or of the TNF receptor superfamily. While naive T cells primarily utilize CD28 as the co-stimulatory receptor, naive B cells use the TNF receptor family member CD40. The overall function of signaling through these co-stimulatory receptors is to enhance the antigen receptor signals that induce transcription factor activation and PI 3-kinase activation, thereby ensuring activation of the T cell or B cell. In contrast to these activating co-stimulatory receptor signals, other cell-surface receptors on T cells and B cells function to downregulate activation signals. These inhibitory receptors are important in preventing excessive immune responses that can lead to destructive inflammatory or autoimmune conditions, particularly in the case of chronic infections that are inefficiently controlled by the immune system.
7-21 The cell-surface protein CD28 is a required co-stimulatory signaling receptor for naive T-cell activation.