Jabara, Haifa H.McDonald, Douglas R.Janssen, ErinMassaad, Michel J.Ramesh, NarayanaswamyBorzutzky, ArturoRauter, IngridBenson, HalliSchneider, LyndaBaxi, SachinRecher, MikeNotarangelo, Luigi D.Wakim, RimaDbaibo, GhassanDasouki, MajedAl-Herz, WaleedBarlan, IsilBaris, SafaKutukculer, NecilOchs, Hans D.Plebani, AlessandroKanariou, MariaLefranc, GerardReisli, IsmailFitzgerald, Katherine AGolenbock, Douglas T.Manis, JohnKeles, SevgiCeja, ReubenChatila, Talal A.Geha, Raif S.2022-08-232022-08-232012-05-132013-01-31Nat Immunol. 2012 May 13;13(6):612-20. doi: 10.1038/ni.2305. <a href="http://dx.doi.org/10.1038/ni.2305" target="_blank">Link to article on publisher's site</a>1529-2908 (Linking)10.1038/ni.230522581261https://hdl.handle.net/20.500.14038/34921The 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.en-USAdolescentAnimalsB-LymphocytesCell DifferentiationChildChild, PreschoolFlow CytometryFocal Adhesion Kinase 2Guanine Nucleotide Exchange FactorsHumansImmunologic MemoryLymphocyte ActivationMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutMyeloid Differentiation Factor 88NeutrophilsPhosphorylationSTAT3 Transcription FactorToll-Like Receptor 9src-Family KinasesImmunology and Infectious DiseaseJournal Articlehttps://escholarship.umassmed.edu/infdis_pp/1463631086infdis_pp/146