The TNF (Tumor Necrosis Factor) and TNF receptor superfamilies (TNFSF and TNFRSF) consist of approximately 50 membrane and soluble proteins that can modulate cellular function. Most of these molecules are expressed by or can target cells of the immune system, and they have a wide range of actions including promoting cellular differentiation, survival,  and production of inflammatory cytokines and chemokines. Members of the TNFRSF (Tumor Necrosis Factor Receptor superfamily) participate prominently in B-cell maturation and function. In particular, BAFFR (B-cell Activating Factor) belonging to the TNF family receptor, BCMA (B-Cell Maturation Antigen), 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 proliferation-inducing ligand APRIL (A Proliferation-Inducing Ligand) and/or BAFF (Ref. 1).

APRIL, also known as TALL2 (TNF- and APOL-related Leukocyte expressed Ligand-2), has no essential function in normal B-cell development and plays only a minor role in B-cell homeostasis. In immune responses, APRIL acts as a costimulator for B- and T-cell proliferation and supports class switching. In general, cytokines of the TNF superfamily are functional both in their membrane-bound and in soluble form when shed by enzymatic cleavage from the surface through a furin-like convertase. APRIL is secreted following intracellular processing in the Golgi apparatus. APRIL binds to two separate receptors, the TACI (Transmembrane Activator and Calcium modulator ligand Interactor), and the BCMA (B Cell Maturation Antigen). Both receptors are expressed on B-cells, although their expression level changes with B-cell maturation (Ref. 2). These receptors are functional as their ligation triggers activation of NF-KappaB, MAPK/JNK and Akt signaling. APRIL may also induce apoptosis through its interaction with other TNF receptor family proteins such as TNFRSF6/FAS and TNFRSF14/HVEM.

Signaling through TACI in mature B-cells or plasmablasts is only achieved by higher-order APRIL oligomers, all of which are potent activators of a multimerization-dependent reporter signaling pathway. TACI intracellular domain interacts with TNFR-associated factor TRAF2, 5, and 6. TRAFs are trimeric intermediates in the signaling pathway of numerous TNF receptor family members. By bringing together the receptors, a trimeric ligand may allow recruitment to the complex of just one intracellular TRAF, which may not be enough to induce signaling, as oligomerization of trimeric TRAF-2 and TRAF-6 is required to activate downstream signaling events (Ref. 3). The cytoplasmic domain of TACI encompasses a conserved motif that binds MyD88, an adaptor that activates transcription factor NF-kB signaling pathways via a Toll–Interleukin 1 (IL-1) receptor (TIR) domain. TACI lacks a TIR domain, yet triggers CSR via the DNA-editing enzyme AID by activating NF-kB through Toll-like receptor (TLR)-like MyD88-IRAK1-IRAK4-TRAF6-TAK1 pathway (Ref. 4 and 5). BCMA binds to APRIL with high affinity. BCMA enhances B-cell antigen presentation by recruiting TRAF proteins and activating NF-KappaB. BCMA might regulate post-CSR events, including the differentiation and survival of mucosal IgA-secreting plasma cells (Ref. 6).




Pathway Key

  1. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Rickert RC, Jellusova J, Miletic AV. Immunol Rev. 2011 Nov;244(1):115-33. doi: 10.1111/j.1600-065X.2011.01067.x.
  2. In vitro and in vivo activation induces BAFF and APRIL expression in B cells. Chu VT, Enghard P, Riemekasten G, Berek C. J Immunol. 2007 Nov 1;179(9):5947-57.
  3. TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts. Bossen C, Cachero TG, Tardivel A, Ingold K, Willen L, Dobles M, Scott ML, Maquelin A, Belnoue E, Siegrist CA, Chevrier S, Acha-Orbea H, Leung H, Mackay F, Tschopp J, Schneider P. Blood. 2008 Feb 1;111(3):1004-12. Epub 2007 Oct 17.
  4. The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. He B, Santamaria R, Xu W, Cols M, Chen K, Puga I, Shan M, Xiong H, Bussel JB, Chiu A, Puel A, Reichenbach J, Marodi L, Döffinger R, Vasconcelos J, Issekutz A, Krause J, Davies G, Li X, Grimbacher B, Plebani A, Meffre E, Picard C, Cunningham-Rundles C, Casanova JL, Cerutti A. Nat Immunol. 2010 Sep;11(9):836-45. Epub 2010 Aug 1.
  5. TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation. Xia XZ, Treanor J, Senaldi G, Khare SD, Boone T, Kelley M, Theill LE, Colombero A, Solovyev I, Lee F, McCabe S, Elliott R, Miner K, Hawkins N, Guo J, Stolina M, Yu G, Wang J, Delaney J, Meng SY, Boyle WJ, Hsu H. J Exp Med. 2000 Jul 3;192(1):137-43.
  6. Innate control of B cell responses. Cerutti A, Puga I, Cols M. Trends Immunol. 2011 May;32(5):202-11. Epub 2011 Mar 16. Review.