caa a22 4500 606177507 CHVBK 20210128100752.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s00018-014-1806-x doi (NATIONALLICENCE)springer-10.1007/s00018-014-1806-x Syk is indispensable for CpG-induced activation and differentiation of human B cells [Elektronische Daten] [Mariann Kremlitzka, Bernadett Mácsik-Valent, Anna Erdei] B cells are efficiently activated by CpG oligodeoxynucleotides (ODNs) to produce pro-inflammatory cytokines and antibody (Ab). Here, we describe a so far unidentified, spleen tyrosine kinase (Syk)-dependent pathway, which is indispensable for CpG-induced human B cell activation. We show that triggering of B cells by CpG results in Syk and src kinase phosphorylation, proliferation, as well as cytokine and Ab production independent of the BCR. Notably, all these functions are abrogated when Syk is inhibited. We demonstrate that CpG-induced Syk activation originates from the cell surface in a TLR9-dependent manner. While inhibition of Syk does not influence the uptake of CpG ODNs, activation of the kinase is a prerequisite for the delivery of CpG into TLR9-containing endolysosomes and for the CpG-induced up-regulation of TLR9 expression. Our results reveal an alternative, Syk-dependent pathway of CpG-induced B cell stimulation, which is initiated at the plasma membrane and seems to be an upstream requirement for endosomal TLR9-driven B cell proliferation and differentiation. Springer Basel, 2014 B cells nationallicence TLR9 nationallicence Syk nationallicence Cell activation nationallicence Signal transduction nationallicence ODN : Oligodeoxynucleotide nationallicence TLR : Toll-like receptor nationallicence MyD88 : Myeloid differentiating factor 88 nationallicence Syk : Spleen tyrosine kinase nationallicence BCR : B cell receptor nationallicence MAPK : Mitogen-activated protein kinase nationallicence LAMP-1 : Lysosome-associated membrane protein-1 nationallicence Kremlitzka Mariann MTA-ELTE Immunology Research Group, Budapest, Hungary aut Mácsik-Valent Bernadett Department of Immunology, Eötvös Loránd University, 1117 Budapest Pázmány s. 1/c, Budapest, Hungary aut Erdei Anna Department of Immunology, Eötvös Loránd University, 1117 Budapest Pázmány s. 1/c, Budapest, Hungary aut Cellular and Molecular Life Sciences Springer Basel 72/11(2015-06-01), 2223-2236 1420-682X 72:11<2223 2015 72 18 https://doi.org/10.1007/s00018-014-1806-x text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1806-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kremlitzka Mariann MTA-ELTE Immunology Research Group, Budapest, Hungary aut NATIONALLICENCE 700 1- Mácsik-Valent Bernadett Department of Immunology, Eötvös Loránd University, 1117 Budapest Pázmány s. 1/c, Budapest, Hungary aut NATIONALLICENCE 700 1- Erdei Anna Department of Immunology, Eötvös Loránd University, 1117 Budapest Pázmány s. 1/c, Budapest, Hungary aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/11(2015-06-01), 2223-2236 1420-682X 72:11<2223 2015 72 18