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

Nat Immunol. 2012 May 13;13(6):612-20. doi: 10.1038/ni.2305.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • B-Lymphocytes / immunology*
  • Cell Differentiation / immunology
  • Child
  • Child, Preschool
  • Flow Cytometry
  • Focal Adhesion Kinase 2 / immunology
  • Guanine Nucleotide Exchange Factors / immunology*
  • Humans
  • Immunologic Memory / immunology*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / immunology*
  • Neutrophils / immunology
  • Phosphorylation
  • STAT3 Transcription Factor / immunology
  • Toll-Like Receptor 9 / immunology*
  • src-Family Kinases / immunology

Substances

  • DOCK8 protein, human
  • Guanine Nucleotide Exchange Factors
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • Focal Adhesion Kinase 2
  • PTK2B protein, human
  • lyn protein-tyrosine kinase
  • src-Family Kinases