Interconnectivity of signaling pathways emanating from TLRs and TACI

Interconnectivity of signaling pathways emanating from TLRs and TACI. DCs activate B cells by releasing BAFF, APRIL, and cytokines upon sensing microbial TLR ligands. Engagement of TACI by BAFF and/or APRIL triggers association of the adaptor MyD88 to a TACI highly conserved (THC) domain that activates NF-κB via IRAK-1, IRAK-4, TAK-1, and IKK-mediated degradation of IκB. Additional NF-κB activation involves binding of TRAF2, TRAF5, and TRAF6 to a TRAF-binding site (TBS) in the cytoplasmic domain of TACI and calcium modulator and cyclophilin ligand (CAML), a transmembrane TACI-interacting protein. NF-κB initiates class switch recombination (CSR) by binding to κB motifs on AICDA and CH gene promoters. Engagement of TLRs by microbial ligands enhances CSR through a TIR-dependent pathway that shares MyD88 with the TIR-independent pathway emanating from TACI. Further CSR-inducing signals are provided by cytokines via signal transducer and activator of transcription (STAT) proteins that bind to γinterferon-activated site (GAS) motifs on AICDA and CH gene promoters. (Additional abbreviations used in figure: APRIL, a proliferation-inducing ligand; BAFF, B cell–activating factor; DC, dendritic cell; IKK, IκB kinase; IRAK, IL-1 receptor–associated kinase; TACI, transmembrane activator and calcium modulator and cyclophylin ligand interactor; TAK, TGF-β-activated kinase; TIR, Toll-interleukin-1 receptor; TLR, Toll-like receptor.)

Publication

Immunoglobulin Responses at the Mucosal Interface. () Andrea Cerutti, et al. Annu Rev Immunol. ;29:273-293. Figure: F3. Homo sapiens

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