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

Abstract

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.

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Figure 1: TACI triggers CSR by acting together with TLR ligands.
Figure 2: TACI interacts with MyD88.
Figure 3: TACI requires MyD88 to activate NF-κB.
Figure 4: TACI binds MyD88 through a THC domain.
Figure 5: TACI signals through a TLR-like pathway.
Figure 6: TACI requires MyD88 to induce CSR in humans.
Figure 7: TACI requires MyD88 to induce CSR in mice.

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Acknowledgements

We thank S.Y. Zhang (University Paris Descartes) for peripheral blood mononuclear cells from patients deficient in the transmembrane protein Unc93b; S. Vogel and A. Medvedev (University of Maryland) for DN-IRAK4-C877T; J.D. Li (University of South California) for DN-IKKα(K44M) and DN-IKKβ(K49A); J. Jun Ninomiya-Tsuji (Lerner Research Institute) for DN-TAK1(K63W); Z. Cao (Tularik) for DN-IRAK1(1–208); and the Mount Sinai School of Medicine Microscopy Shared Resource Facility. Supported by the US National Institutes of Health (R01 AI-05753 and R01 AI-074378 to A. Cerutti and S10RR09145), Catalan Institute for Research and Advanced Studies (A. Cerutti), Fundacio' Institut Municipal d'Investigació Mèdica (A. Cerutti), Ministerio de Ciencia e Innovación (SAF 2008-02725 to A. Cerutti), The Irma T. Hirschl Charitable Trust (A. Cerutti), Comissionat per a Universitats i Recerca del Departament d'Innovació, Universitats i Empresa de la Generalitat de Catalunya (R.S.), Programa Juán de la Cierva (I.P.), Fondazione C. Golgi and Centro Immunodeficienze Mario di Martino (A. Plebani), TÁMOP (4.2.2-08/1-2008-0015 to L.M.), the US National Institutes of Health–National Cancer Institute (5R24 CA095823) and the National Science Foundation (DBI-9724504).

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B.H., R.S., W.X., M.C., K.C., I.P., M.S. and E.M. designed and did research; H.X. provided spleens from wild-type and MyD88-deficient mice; J.B.B., A. Chiu, A. Puel, J.R., L.M., R.D., J.V., A.I., J.K., G.D., B.G. and C.P. provided blood and tissue samples; X.L. provided reagents, including MyD88-deficient 293 cells; A. Plebani, C.C.-R. and J.-L.C. provided blood samples, tissue samples and clinical information and discussed data; and A. Cerutti designed research, discussed data and wrote the paper.

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Correspondence to Andrea Cerutti.

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He, B., Santamaria, R., Xu, W. et al. The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nat Immunol 11, 836–845 (2010). https://doi.org/10.1038/ni.1914

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