title: DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation.
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.
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Haifa H
authors.initials: HH
authors.lastname: Jabara
authors.forename: Douglas R
authors.initials: DR
authors.lastname: McDonald
authors.forename: Erin
authors.initials: E
authors.lastname: Janssen
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Massaad
authors.forename: Narayanaswamy
authors.initials: N
authors.lastname: Ramesh
authors.forename: Arturo
authors.initials: A
authors.lastname: Borzutzky
authors.forename: Ingrid
authors.initials: I
authors.lastname: Rauter
authors.forename: Halli
authors.initials: H
authors.lastname: Benson
authors.forename: Lynda
authors.initials: L
authors.lastname: Schneider
authors.forename: Sachin
authors.initials: S
authors.lastname: Baxi
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Rima
authors.initials: R
authors.lastname: Wakim
authors.forename: Ghassan
authors.initials: G
authors.lastname: Dbaibo
authors.forename: Majed
authors.initials: M
authors.lastname: Dasouki
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.forename: Isil
authors.initials: I
authors.lastname: Barlan
authors.forename: Safa
authors.initials: S
authors.lastname: Baris
authors.forename: Necil
authors.initials: N
authors.lastname: Kutukculer
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: Maria
authors.initials: M
authors.lastname: Kanariou
authors.forename: Gerard
authors.initials: G
authors.lastname: Lefranc
authors.forename: Ismail
authors.initials: I
authors.lastname: Reisli
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Douglas
authors.initials: D
authors.lastname: Golenbock
authors.forename: John
authors.initials: J
authors.lastname: Manis
authors.forename: Sevgi
authors.initials: S
authors.lastname: Keles
authors.forename: Reuben
authors.initials: R
authors.lastname: Ceja
authors.forename: Talal A
authors.initials: TA
authors.lastname: Chatila
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000293:Adolescent; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005434:Flow Cytometry; D051418:Focal Adhesion Kinase 2 / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology*; D019061:src-Family Kinases / Q000276:immunology
chemical_list: C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D051418:Focal Adhesion Kinase 2; C103547:PTK2B protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases