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
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.
Jabara, Haifa H.; McDonald, Douglas R.; Janssen, Erin; Massaad, Michel J.; Ramesh, Narayanaswamy; Borzutzky, Arturo; Rauter, Ingrid; Benson, Halli; Schneider, Lynda; Baxi, Sachin; Recher, Mike; Notarangelo, Luigi D.; Wakim, Rima; Dbaibo, Ghassan; Dasouki, Majed; Al-Herz, Waleed; Barlan, Isil; Baris, Safa; Kutukculer, Necil; Ochs, Hans D.; Plebani, Alessandro; Kanariou, Maria; Lefranc, Gerard; Reisli, Ismail; Fitzgerald, Katherine A.; Golenbock, Douglas T.; Manis, John; Keles, Sevgi; Ceja, Reuben; Chatila, Talal A.; and Geha, Raif S., "DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation" (2012). Infectious Diseases and Immunology Publications and Presentations. 146.