Hetero-oligomerization between the TNF receptor superfamily members CD40, Fas and TRAILR2 modulate CD40 signalling

Abstract

TNF receptor superfamily members (TNFRSF) such as CD40, Fas and TRAIL receptor 2 (TRAILR2) participate to the adaptive immune response by eliciting survival, proliferation, differentiation and/or cell death signals. The balance between these signals determines the fate of the immune response. It was previously reported that these receptors are able to self-assemble in the absence of ligand through their extracellular regions. However, the role of this oligomerization is not well understood, and none of the proposed hypotheses take into account potential hetero-association of receptors. Using CD40 as bait in a flow cytometry Förster resonance energy transfer assay, TNFRSF members with known functions in B cells were probed for interactions. Both Fas and TRAILR2 associated with CD40. Immunoprecipitation experiments confirmed the interaction of CD40 with Fas at the endogenous levels in a BJAB B-cell lymphoma cell line deficient for TRAILR2. TRAILR2-expressing BJAB cells displayed a robust CD40–TRAILR2 interaction at the expense of the CD40–Fas interaction. The same results were obtained by proximity ligation assay, using TRAILR2-positive and -negative BJAB cells and primary human B cells. Expression of the extracellular domains of Fas or TRAILR2 with a glycolipid membrane anchor specifically reduced the intrinsic signalling pathway of CD40 in 293T cells. Conversely, BJAB cells lacking endogenous Fas or TRAILR2 showed an increased NF-κB response to CD40L. Finally, upregulation of TRAILR2 in primary human B cells correlated with reduced NF-κB activation and reduced proliferation in response to CD40L. Altogether, these data reveal that selective interactions between different TNFRSF members may modulate ligand-induced responses upstream signalling events.

Microvesicles produced by natural killer cells of the NK-92 cell line affect the phenotype and functions of endothelial cells of the EA.Hy926 cell line

“…The exogenous pathway is accomplished by ligand binding to a receptor on the cell surface. These receptors include the TNFα superfamily of Fas (CD95), TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4 [70], TNF-R1 (CD120a) [76], DR5 (death receptor 5), and DR6 (death receptor 6) [3]. Ligand-receptor interactions lead to activation of an intracellular reaction cascade involving caspase-8 activating effector caspase-3, caspase-6 and caspase-7, which ensures cell death [3,78].…”

Age-Related Changes on CD40 Promotor Methylation and Immune Gene Expressions in Thymus of Chicken

“…By interaction with CD40L, CD40 could modulate the crosstalk between antigen presenting cells (macrophages and dendritic cell) and T/B cell, and further induce the expression of pro-inflammatory cytokines and activation of B cell response ( 52 ), as well as synthesis of IgG/A ( 50 , 53 ). As a key co-stimulatory molecule in T cell, CD40 is critical for body's defense against invading pathogens, and plays essential role in adaptive immunity by eliciting survival, proliferation, differentiation and/or cell death signaling pathways ( 54 , 55 ), and so, contributes much to immune response against pathogen infection ( 56 ), however, these immune responses often accompany inflammatory response ( 56 – 58 ). CD40 and CD40 ligand (CD40L) participate in numerous inflammatory pathways, as well as oxidative stress ( 50 ).…”

BAFF and BAFF-Receptor in B Cell Selection and Survival

“…Structurally, BAFFR is an atypical representative of the TNF-receptor super-family. Members of this family are typically characterized by several extracellular cysteine-rich domains (CRDs), which serve for ligand binding as well as for ligand-independent assembly of receptor monomers into dimers, trimers or multimers ( 1 – 6 ). Unlike most other TNF-R family members, BAFFR contains only a partial CRD which serves for ligand binding as well as for self-assembly ( 7 ).…”