The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88.
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-kappaB 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-kappaB 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.
He
Bing
B
Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Santamaria
Raul
R
Xu
Weifeng
W
Cols
Montserrat
M
Chen
Kang
K
Puga
Irene
I
Shan
Meimei
M
Xiong
Huabao
H
Bussel
James B
JB
Chiu
April
A
Puel
Anne
A
Reichenbach
Jeanine
J
Marodi
László
L
Döffinger
Rainer
R
Vasconcelos
Julia
J
Issekutz
Andrew
A
Krause
Jens
J
Davies
Graham
G
Li
Xiaoxia
X
Grimbacher
Bodo
B
Plebani
Alessandro
A
Meffre
Eric
E
Picard
Capucine
C
Cunningham-Rundles
Charlotte
C
Casanova
Jean-Laurent
JL
Cerutti
Andrea
A
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D015398:Signal Transduction; D053303:Transmembrane Activator and CAML Interactor Protein / Q000276:immunology*
D053594:Myeloid Differentiation Factor 88; D053303:Transmembrane Activator and CAML Interactor Protein