DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation
Department of Medicine, Division of Infectious Diseases and Immunology
Adolescent; Animals; B-Lymphocytes; Cell Differentiation; Child; Child, Preschool; Flow Cytometry; Focal Adhesion Kinase 2; Guanine Nucleotide Exchange Factors; Humans; Immunologic Memory; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Neutrophils; Phosphorylation; STAT3 Transcription Factor; Toll-Like Receptor 9; src-Family Kinases
Immunology and Infectious Disease
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-kappaB, 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.
DOI of Published Version
Nat Immunol. 2012 May 13;13(6):612-20. doi: 10.1038/ni.2305. Link to article on publisher's site
Jabara HH, McDonald DR, Janssen E, Massaad MJ, Ramesh N, Borzutzky A, Rauter I, Benson H, Schneider L, Baxi S, Recher M, Notarangelo LD, Wakim R, Dbaibo G, Dasouki M, Al-Herz W, Barlan I, Baris S, Kutukculer N, Ochs HD, Plebani A, Kanariou M, Lefranc G, Reisli I, Fitzgerald KA, Golenbock DT, Manis J, Keles S, Ceja R, Chatila TA, Geha RS. (2012). DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Infectious Diseases and Immunology Publications. https://doi.org/10.1038/ni.2305. Retrieved from https://escholarship.umassmed.edu/infdis_pp/146