Signaling through the antigen receptors on T cells and B cells is essential for the activation of these cells. However, for naive T and B cells, the signal through the T-cell receptor or B-cell receptor, respectively, is not sufficient to initiate a response. In addition to the antigen receptor signals, these cells require signals through accessory receptors that serve to monitor the environment of the cell to ensure the presence of an infection. An important secondary signaling
Fig. 7.34 The ITIM-containing Fc receptor inhibits B-cell receptor signaling by recruiting the inositol phosphatase SHIP. When the B-cell receptor binds an antigen that is already present in immune complexes with igG, the iTim-containing fc receptor fcγRiiB is engaged at the same time as the B-cell receptor. The Src-family kinase present at the B-cell receptor (BcR) phosphorylates the iTim motif of fcγRiiB, which then recruits the Sh2 domain-containing inositol phosphatase Ship. Ship dephosphorylates pip3 in the plasma membrane, generating pip2. ph domain-containing enzymes, such as vav, Btk, and pLc-γ, depend on their ph domain binding to pip3 for their stable recruitment to the activated B-cell receptor complex. The loss of pip3 terminates the recruitment of these enzymes and inhibits B-cell receptor signaling.
system in naive T cells is provided by the CD28 family of co-stimulatory proteins, which bind members of the B7 family of proteins. Activating members of the CD28 family provide co-stimulatory signals that amplify the signal from the T-cell receptor and are important in ensuring the activation of naive T cells by the appropriate target cell. In B cells, these secondary signals are provided by members of the TNF receptor superfamily, such as CD40. Inhibitory members of the CD28 and other receptor families function to attenuate or completely block signaling by activating receptors. The regulated expression of activating and inhibitory receptors and their ligands generates a sophisticated level of control of immune responses that is only beginning to be understood.
Summary to Chapter 7.
Signaling by cell-surface receptors of many different sorts is crucial to the ability of the immune system to respond appropriately to foreign pathogens. The importance of these signaling pathways is demonstrated by the many diseases that are due to aberrant signaling, which include both immunodeficiency diseases and autoimmune diseases. Common features of many signaling pathways are the generation of second messengers such as calcium and phosphoinositides and the activation of both serine/threonine and tyrosine kinases. An important concept in the initiation of signaling pathways by receptor proteins is the recruitment of signaling proteins to the plasma membrane and the assembly of multiprotein signaling complexes. In many cases, signal transduction leads to the activation of transcription factors that lead directly or indirectly to the proliferation, differentiation, and effector function of activated lymphocytes. Other roles of signal transduction are to mediate changes in the cytoskeleton that are important for cell functions such as migration and shape changes. These steps of the T-cell and B-cell receptor signaling pathways are summarized in Fig. 7.28.
While we are beginning to understand the basic circuitry of signal transduction pathways, it is important to keep in mind that we do not yet understand why these pathways are so complex. One reason might be that the signaling pathways have roles in properties such as amplification, robustness, diversity, and efficiency of signaling responses. An important goal for the future will be to understand how the design of each signaling pathway contributes to the particular quality and sensitivity needed for specific signaling responses.
Questions.
7.1 True or False: antigen receptors bear intrinsic kinase activity that allows for phosphorylation of cytoplasmic proteins and subsequent downstream signaling events.