期刊
NATURE IMMUNOLOGY
卷 13, 期 6, 页码 612-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.2305
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资金
- US Public Health Service [P01AI076210, T32AI007512, R01AI083503, R21AI087627, K08AI076625]
- Dubai Harvard Foundation for Medical Research
- Swiss National Science Foundation [PASMP3-127678/1]
- Clinical Immunology Society
- Manton Foundation
- Swiss National Science Foundation (SNF) [PASMP3-127678] Funding Source: Swiss National Science Foundation (SNF)
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-kappa B, 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.
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