Fig. 7.29 The T-cell co-stimulatory protein CD28 transduces signals that enhance antigen receptor signaling pathways. The ligands for cd28, namely B7.1 and B7.2, are expressed only on specialized antigen-presenting cells (apcs) such as dendritic cells (first panel). engagement of cd28 induces its tyrosine phosphorylation, which activates pi 3-kinase (pi3K), with subsequent production of pip3 that recruits several enzymes via their ph domains, thus bringing them together with their substrates in the membrane. The protein kinase akt, which becomes phosphorylated by phosphoinositide-dependent protein kinase-1 (pdK1), is activated and enhances cell survival and upregulates cell metabolism (see fig. 7.22). Recruitment of the kinase itk to the membrane is critical for the full activation of pLc-γ (see fig. 7.16). pip3 also recruits vav, leading to cdc42 activation and inducing actin polymerization (see fig. 7.24).
7-22 Maximal activation of PLC-γ, which is important for transcription factor activation, requires a co-stimulatory signal induced by CD28.
One important function of co-stimulatory signaling through CD28 is to promote the maximal activation of PLC-γ via the local production of PIP3. This recruits Itk by its PH domain, enhancing Itk phosphorylation by Lck. Activated Itk is then recruited to the phosphorylated LAT:Gads:SLP-76 complex by its SH2 and SH3 domains binding to SLP-76, where it phosphorylates and activates PLC-γ (see Fig. 7.16). Activated PLC-γ cleaves PIP2 to produce the two second messengers DAG and IP3, ultimately leading to the activation of transcription factors NFAT, AP-1, and NFκB. Thus, the full activation of PLC-γ leading to transcription factor activation requires signals emanating from both the T-cell receptor and CD28.
In T cells, one of the major functions of NFAT, AP-1, and NFκB is to act together to stimulate expression of the gene for the cytokine IL-2, which is essential for promoting T-cell proliferation and differentiation into effector cells. The promoter for the IL-2 gene contains multiple regulatory elements that must be bound by transcription factors to initiate IL2 expression. Some control sites are already bound by transcription factors, such as Oct1, that are produced constitutively in lymphocytes, but this is not sufficient to switch on IL-2. Only when AP-1, NFAT, and NFκB are all activated and are bound to their control sites in the IL-2 promoter is the gene expressed. NFAT and AP-1 bind to the promoter cooperatively and with higher affinity by forming a heterotrimer of NFAT, Jun, and Fos. In addition, CD28 co-stimulation further enhances IL-2 transcription by increasing NFκB activation. Thus, the IL-2 promoter integrates signals from both the T-cell receptor and CD28 signaling pathways to ensure that IL-2 is produced only in appropriate circumstances (Fig. 7.30). Together with the CD28-induced phosphorylation of NF-90 leading to increased IL-2 mRNA stability, CD28 co-stimulation leads to substantially increased production of IL-2 by activated T cells.
7-23 TNF receptor superfamily members augment T-cell and B-cell activation.
While naive Tand B-cell activation requires signaling through the antigen receptors on these cells, T-cell receptor or B-cell receptor signaling,
Fig. 7.30 Simplified scheme depicting multiple signaling pathways that converge on the IL-2 promoter.