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DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation

2012; Nature Portfolio; Volume: 13; Issue: 6 Linguagem: Inglês

10.1038/ni.2305

1529-2916

Haifa H. Jabara, Douglas R. McDonald, Erin Janssen, Michel J. Massaad, Narayanaswamy Ramesh, Arturo Borzutzky, Ingrid Rauter, Halli Benson, Lynda C. Schneider, Sachin N. Baxi, Mike Recher, Luigi D. Notarangelo, Rima Hanna Wakim, Ghassan Dbaibo, Majed Dasouki, Waleed Al‐Herz, Işıl Barlan, Safa Barış, Necil Kütükçüler, Hans D. Ochs, Alessandro Plebani, Maria Kanariou, Marie‐Paule Lefranc, İsmail Reisli, Katherine A. Fitzgerald, Douglas T. Golenbock, John P. Manis, Sevgi Keleş, Reuben Ceja, Talal A. Chatila, Raif S. Geha,

T-cell and B-cell Immunology

Dock8 deficiency leads to defects in humoral immunity. Geha and colleagues show that Dock88 interacts with MyD88 to bridge TLR9 signaling to the Src-Syk-STAT3 pathway to promote B cell proliferation and differentiation. The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27+ memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-κB, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src–kinase Syk–transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.