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The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88

2010; Nature Portfolio; Volume: 11; Issue: 9 Linguagem: Inglês

10.1038/ni.1914

1529-2916

Bing He, Raül Santamaría, Weifeng Xu, Montserrat Cols, Kang Chen, Irene Puga, Meimei Shan, Huabao Xiong, James B. Bussel, April Chiu, Anne Puel, Janine Reichenbach, László Maródi, Rainer Döffinger, Júlia Vasconcelos, Andrew C. Issekutz, Jens C. Krause, Graham Davies, Xiaoxia Li, Bodo Grimbacher, Alessandro Plebani, Eric Meffre, Capucine Pïcard, Charlotte Cunningham‐Rundles, Jean‐Laurent Casanova, Andrea Cerutti,

Immune Response and Inflammation

Immunoglobulin class-switch recombination can be induced by the secreted factors BAFF and APRIL. Cerutti and colleagues show that the receptor TACI conveys such signals via the adaptor MyD88 to induce class-switch recombination. BAFF and APRIL are innate immune mediators that trigger immunoglobulin G (IgG) and IgA class-switch recombination (CSR) in B cells by engaging the receptor TACI. The mechanism that underlies CSR signaling by TACI remains unknown. Here we found that the cytoplasmic domain of TACI encompasses a conserved motif that bound MyD88, an adaptor that activates transcription factor NF-κB signaling pathways via a Toll–interleukin 1 (IL-1) receptor (TIR) domain. TACI lacks a TIR domain, yet triggered CSR via the DNA-editing enzyme AID by activating NF-κB through a Toll-like receptor (TLR)-like MyD88-IRAK1-IRAK4-TRAF6-TAK1 pathway. TACI-induced CSR was impaired in mice and humans lacking MyD88 or the kinase IRAK4, which indicates that MyD88 controls a B cell–intrinsic, TIR-independent, TACI-dependent pathway for immunoglobulin diversification.