Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease

Abstract

Members of the tumor necrosis factor receptor superfamily (TNFRSF) participate prominently in B-cell maturation and function. In particular, B-cell activating factor belonging to the TNF family receptor (BAFF-R), B-cell maturation antigen (BCMA), and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) play critical roles in promoting B-cell survival at distinct stages of development by engaging a proliferation-inducing ligand (APRIL) and/or BAFF. CD40 is also essential for directing the humoral response to T-cell-dependent antigens. Signaling by the TNFRSF is mediated primarily, albeit not exclusively, via the TNFR-associated factor (TRAF) proteins and activation of the canonical and/or non-canonical nuclear factor-κB (NF-κB) pathways. Dysregulated signaling by TNFRSF members can promote B-cell survival and proliferation, causing autoimmunity and neoplasia. In this review, we present a current understanding of the functions of and distinctions between APRIL/BAFF signaling by their respective receptors expressed on particular B-cell subsets. These findings are compared and contrasted with CD40 signaling, which employs similar signaling conduits to achieve distinct cellular outcomes in the context of the germinal center response. We also underscore how new findings and conceptual insights into TNFRSF signaling are facilitating the understanding of B-cell malignancies and autoimmune diseases.

Fig. 1. Role of signaling mediated by different members of the TNF receptor family during B-cell maturation and differentiation

B cells develop in the bone marrow and migrate to the periphery. After stimulation, mature B cells differentiate into germinal center B cells, memory B cells, and plasma cells. Some plasma cells re-enter the bone marrow where they find the microenvironment supporting their longterm survival. The figure shows stages of B-cell maturation and differentiation affected by the mutation or loss of different TNF receptors (in blue rectangles) their ligands (in red rectangles) or members of the NFκB pathway (in green rectangles).

Fig. 2. Model depicting the canonical and non-canonical NFκB pathway

Activation of the IKK complex in the canonical pathway leads to the phosphorylation and ubiqutination of IκB, which is subsequently cleaved in the proteasome. The freed NFκB dimers are now able to enter the nucleus. NIK mediated IKK1 phosphorylation leads to the activation of the non-canonical pathway which is characterized by the cleavage of p100 and release of the NFκB heterodimer p52/RelB.

Fig. 3. BAFF, APRIL, and their receptors

Schematic of the binding of the various forms of B-cell activating factor belonging to the TNF family (BAFF) and APRIL (a proliferation-inducing ligand), to their receptors, BAFF receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antigen (BCMA). (A) BAFF is synthesized as a membrane-bound protein that can be released as a soluble cytokine via proteolytic cleavage by furin proteases. Soluble BAFF exists in two forms: as a homotrimer or as an assembly of 20 trimers that form a 60-mer. The BAFF trimer can bind BAFF-R, APRIL, and BCMA while oligomeric 60-mer BAFF can bind to BAFF-R, TACI, and also with low affinity to BCMA. (B) APRIL is also synthesized as a membrane-bound protein that can be released as a soluble cytokine by furin protease cleavage and forms soluble trimers. APRIL binds to sulphated side chains of heparan sulphate proteoglycan (HSPG) at a site distinct from the site it uses to bind to TACI and BCMA.

Fig. 4. Signaling and crosstalk between the BCR and BAFF-R

Signaling via the BCR and BAFF-R are both critical for B-cell maturity and homeostasis. Phosphorylation of tyrosine residues in the immunoreceoptor tyrosine activation motifs (ITAMs) of the cytoplasmic tails of BCR-associated Igα and Igβ chains initiates BCR-proximal signaling and the formation of an active signalosome. Phosphorylation of ITAM tyrosines by Src family kinases leads to the recruitment and activation of the kinase Syk and the Tec family kinase BTK, as well as phosphorylation and recruitment of the adaptor BLNK and the lipase PLCγ2. The assembly of an active BCR-proximal signaling complex ultimately leads to activation of MAPKs (not pictured) and canonical NFκB signaling via PKCβ and the CARMA1-MALT1-BCL10 complex which functions to activate IKK1/IKK2. Activation of the IKK1-IKK2-NEMO complex results in phosphorylation of IκBα, marking it for ubiquitination and proteosomal degradation. Activation of canonical NFκB signaling by the BCR leads to induction of transcription of p100, BAFF-R, and cRel (among others), which are critical for BAFF-R signaling. The CD19 coreceptor molecule promotes activation of the PI3K pathway leading to activation of AKT. AKT activation promotes B-cell survival and metabolism through the inhibition of FOXO1, upregulation of MCL-1 and inhibition of BIM, as well as activation of the mTORC1 complex. BAFF-R signaling also activates PI3K (via an unknown mechanism), as well as non-canonical NFκB signaling. Following BAFF engagement of the BAFF-R, TRAF2 and TRAF3 are recruited leading to the release of NIK, which phosphorylates IKK1 leading to p100 processing to p52 and activation of non-canonical NFκB.

Fig. 5. Signaling differences and similarities between CD40 and BAFF-R

Both BAFF-R and CD40 signaling utilize TRAF molecules to promote activation of NFκB. In the case of BAFF-R, direct binding of TRAF3 initiates a cascade resulting in release of NIK and downstream activation of non-canonical NFκB. In this regard, recruitment of a complex containing TRAF3- TRAF2-cIAP1/2-NIK leads to TRAF3 degradation via TRAF2-activated cIAP1/2. Alternatively, NIK can be released from the TRAF3-TRAF2-cIAP1/2-NIK complex via displacement of cAP1/2 and NIK from TRAF2 and TRAF3 which are then degraded. NIK then functions to activate IKK2 resulting in non-canonical NFκB signaling. Upon CD40L engagement of CD40, TRAF2 activation of cIAP can not only lead to activation of NIK but also of MEKK, promoting downstream MAPK signaling. In addition, TRAF6 recruitment results in the activation of the TAB1-TAK complex, which is also responsible for activation of the canonical NFκB pathway.