Molecular mechanism and function of CD40/CD40L engagement in the immune system - PubMed (original) (raw)

Review

Molecular mechanism and function of CD40/CD40L engagement in the immune system

Raul Elgueta et al. Immunol Rev. 2009 May.

Abstract

During the generation of a successful adaptive immune response, multiple molecular signals are required. A primary signal is the binding of cognate antigen to an antigen receptor expressed by T and B lymphocytes. Multiple secondary signals involve the engagement of costimulatory molecules expressed by T and B lymphocytes with their respective ligands. Because of its essential role in immunity, one of the best characterized of the costimulatory molecules is the receptor CD40. This receptor, a member of the tumor necrosis factor receptor family, is expressed by B cells, professional antigen-presenting cells, as well as non-immune cells and tumors. CD40 binds its ligand CD40L, which is transiently expressed on T cells and other non-immune cells under inflammatory conditions. A wide spectrum of molecular and cellular processes is regulated by CD40 engagement including the initiation and progression of cellular and humoral adaptive immunity. In this review, we describe the downstream signaling pathways initiated by CD40 and overview how CD40 engagement or antagonism modulates humoral and cellular immunity. Lastly, we discuss the role of CD40 as a target in harnessing anti-tumor immunity. This review underscores the essential role CD40 plays in adaptive immunity.

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Figures

Fig. 1

Fig. 1. CD40 signaling dependent and independent of tumor necrosis factor receptor-associated factor (TRAF) proteins

After CD40 activation, TRAFs 1, 2, 3, 5, and 6 are recruited to CD40 tail, driving different signaling pathways. Furthermore, Janus family kinase 3 can bind to the proximal cytoplasmic membrane of CD40. The signaling dependent or independent of TRAF protein regulates different cellular and immune processes.

Fig. 2

Fig. 2. Role of tumor necrosis factor receptor-associated factors (TRAFs) 2 and 3 in the inhibition of non-canonical nuclear factor κB (NFκB) pathway

Under non-stimulation, TRAF2 and TRAF3 form a complex with cellular inhibitor of apoptosis 1 and 2 (cIAP1 and cIAP2) and NFκB-inducing kinase (NIK). cIAP1/2 degrades NIK, ablating the non-canonical NFκB pathway (39, 40). After CD40/CD40L engagement, the complex is destabilized, permitting the release of NIK from the complex inducing the non-canonical NFκB signaling. Furthermore, it induced the recruitment of TRAF2 and TRAF3 to CD40 tail and the degradation of TRAF3 by cIAP1/2 proteins.

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