ap-1, nfaT, and nfκB binding to the promoter of the IL-2 gene integrate multiple signaling pathways emanating from the T-cell receptor (TcR) and cd28 into a single output, the production of the cytokine iL-2. The mapK pathway activates ap-1; calcium activates nfaT; and protein kinase c activates nfκB. all three pathways are required to stimulate IL-2 transcription. activation of the gene requires both the binding of nfaT and ap-1 to a specific promoter element, and the additional binding of ap-1 on its own to another site. oct1 is a transcription factor that is required for IL-2 transcription. unlike the other transcription factors, it is constitutively bound to the promoter and is therefore not regulated by T-cell receptor or cd28 signaling.
respectively, is not sufficient to activate the cells. For naive T cells, an additional co-stimulatory signal is required and, as discussed above (see Sections 7-21 and 7-22), is frequently provided by the CD28 receptor. For naive B cells, the additional activation signal can be contributed by direct interactions between the pathogen and an innate pattern recognition receptor (PRR), such as a TLR, on the B cell. However, for more effective B-cell activation leading to the production of all classes of antibodies and to the formation of memory B cells, additional B-cell activation signals are contributed by CD4 T cells. One component of this is the production of T-cell cytokines, which bind to and stimulate their receptors on the B-cell surface (see Chapter 10). The second and more essential component provided by the CD4 T cells is the stimulation of CD40 on the B cell by the CD40 ligand expressed on the T cell. The importance of the CD40–CD40-ligand interaction for B-cell responses to protein antigens is highlighted by the discovery that a severe immunodeficiency disease resulting from impaired antibody responses is caused by the absence of CD40 ligand expression on a patient’s CD4 T cells.
CD40 is a member of the large TNF receptor superfamily, which consists of more than 20 members. While some members of this family, such as Fas (see Chapter 11), are specialized to induce cell death, the majority of TNF receptor superfamily members, including CD40, activate both the NFκB and the PI 3-kinase pathways following receptor stimulation (Fig. 7.31). While NFκB activation leads to enhanced cell survival, the PI 3-kinase pathway has widespread and pleiotropic effects on B-cell physiology, and is a central feature of CD40 signaling. The major mediator of the PI 3-kinase signal is the serine/threonine kinase Akt, which is recruited and activated following the generation of PI(3,4,5)P3 at the B-cell membrane. Akt then stimulates multiple downstream pathways that induce cell survival, cell cycle progression, glucose uptake and metabolism, and mTOR activation, all of which are essential for the productive response of the activated B cell. In general terms, CD40 on the B cell functions in a manner analogous to CD28 on the T cell, as both receptors serve to enhance the levels of Akt activation induced by the B-cell receptor or T-cell receptor signaling pathways, respectively.
TNF receptor superfamily members, including CD40, signal by a mechanism distinct from that of antigen receptors, as it does not involve the activation of tyrosine kinases. Instead, stimulation of TNF receptors recruits adaptor proteins known as TRAFs (TNF receptor-associated factors). In addition to serving as simple adaptors that promote the assembly of multiprotein complexes, five