CD40 Signaling

CD40 conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death. Binding of CD40 with its counter receptor, CD154, acts on antigen presenting cells (APC) and T-Cells in a bi-directional fashion, mediating both humoral and cellular immune responses. On the surface of dendritic cells, CD40-CD40L ligation regulates production of certain proinflammatory cytokines such as IL-8, MIP-1α, TNF-α and IL-12. Ligation of CD40 on monocytes is important in stimulating production of IL-1α, IL-1β, TNF-α, IL-6, and IL-8, as well as in the rescue of circulating monocytes from apoptotis.CD40-mediated signal transduction induces the transcription of a large number of genes implicated in host defense against pathogens. This is accomplished by the activation of multiple pathways including NF-κB, MAPK and STAT3 which regulate gene expression through activation of c-Jun, ATF2 and Rel transcription factors. Receptor clustering of CD40L is mediated by an association of the ligand with p53, a translocation of ASM to the plasma membrane, activation of ASM, and formation of ceramide. Ceramide serves to cluster CD40L and several TRAF proteins (including TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6) with CD40. TRAF2, TRAF3 and TRAF6 bind to CD40 directly. TRAF1 does not directly bind CD40 but is recruited to membrane micro domains through heterodimerization with TRAF2. Analogous to the recruitment of TRAF1,TRAF5 is also indirectly recruited to CD40 in a TRAF3-dependent manner. Act1 links TRAF proteins to TAK1/IKK to activate NF-κB/I-κB, and MKK complex to activate JNK, p38 MAPK and ERK1/2. NIK also plays a leading role in activating IKK. Act1-dependent CD40-mediated NF-κB activation protects cells from CD40L-induced apoptosis. On stimulation with CD40L or other inflammatory mediators, I-κB proteins are phosphorylated by IKK and NF-κB is activated through the Act1-TAK1 pathway. Phosphorylated I-κB is then rapidly ubiquitinated and degraded. The liberated NF-κB translocates to the nucleus and activates transcription. A20, which is induced by TNF inhibits NF-κB activation as well as TNF-mediated apoptosis. TRAF3 initiates signaling pathways that lead to the activation of p38 and JNK but inhibits Act1-dependent CD40-mediated NF-κB activation and initiates CD40L-induced apoptosis. TRAF2 is required for activation of SAPK pathways and also plays a role in CD40-mediated surface upregulation, IgM secretion in B-Cells and up-regulation of ICAM1. CD40 ligation by CD40L stimulates MCP1 and IL-8 production in primary cultures of human proximal tubule cells, and this occurs primarily via recruitment of TRAF6 and activation of the ERK1/2, SAPK/JNK and p38 MAPK pathways. Activation of SAPK/JNK and p38 MAPK pathways is mediated via TRAF6 whereas ERK1/2 activity is potentially mediated via other TRAF members. However, stimulation of all three MAPK pathways is required for MCP1 and IL-8 production. Other pathways activated by CD40 stimulation include the JAK3-STAT3 and PI3K-Akt pathways, which contribute to the anti-apoptotic properties conferred by CD40L to B-Cells. CD40 directly binds to JAK3 and mediates STAT3 activation followed by up-regulation of ICAM1, CD23, and LT-α.CD40L has already been used in the treatment of tumors, and tumor regression is linked to restoration of MHC1 expression by tumor cells, IL-12 overproduction, and potentiation of host APC function. Moreover, CD40 engagement restores production of IL-12 in cells from HIV-infected patients, and it stimulates macrophages to produce HIV1-suppressive chemokines. Activation of the immune system through CD40 ligation provides a potent strategy for immunotherapy of parasitic diseases.