Fig. 7.31 The TNF receptor superfamily member CD40 is an important co-stimulatory molecule on B cells. Several members of the Tnf receptor superfamily are expressed on T cells and B cells. a key function of these receptors is the activation of nfκB, which occurs by a pathway distinct from the one initiated by antigen receptor stimulation and is often referred to as the non-canonical nfκB pathway. Tnf receptor superfamily members also activate pi 3-kinase signaling pathways. one important Tnf receptor superfamily member on B cells is cd40. prior to stimulation, TRaf molecules, which are ubiquitin ligases, are associated with ciap, another ubiquitin ligase, and the nfκB-inducing kinase niK. under these steady-state conditions, TRaf binding promotes ubiquitination and degradation of niK. When cd40 is stimulated by binding to cd40L, this complex is recruited to the intracellular domain of cd40. TRaf2 catalyzes K63-linked ubiquitination of ciap, leading to ciap-mediated K48-linked ubiquitination of TRaf3. This leads to TRaf3 degradation, releasing niK, and allowing niK to phosphorylate and activate iκB kinase α (iKKα). iKKα phosphorylates the nfκB precursor protein p100, inducing its cleavage to form the active p52 subunit, which binds to relB to form the active nfκB transcription factor. cd40L stimulation of cd40 also activates pi 3-kinase, which leads to the activation of akt by pdK1.
of the six known TRAFs also function as E3 ubiquitin ligases. This activity contributes to the ability of most TNF receptor superfamily members to activate the NFκB pathway, using a pathway distinct from the one initiated by antigen receptor stimulation and often referred to as the non-canonical NFκB pathway (see Fig. 7.31). In contrast, the precise biochemical mechanism by which TNF receptors and TRAFs induce PI 3-kinase activation is not yet known.
CD40 is constitutively expressed on B cells and functions during B-cell activation in response to antigen recognition by the B-cell receptor. Additional TNF receptor superfamily members are also expressed on B cells, and each of them is important in B-cell survival at a particular stage of B-cell maturation, including B cells that have differentiated into antibody-secreting cells or memory cells. Similarly, TNF receptor superfamily members are expressed on T cells, many of which are upregulated following T-cell activation. These molecules, such as OX40, 4-1BB, CD30, and CD27, contribute important survival signals and function to enhance cellular metabolism at later stages of the T-cell response to infection (see Chapter 11).
responses by interfering with co-stimulatory signaling pathways.