Bruton's tyrosine kinase mediates the synergistic signalling between TLR9 and the B cell receptor by regulating calcium and calmodulin

Elaine F Kenny; Susan R Quinn; Sarah L Doyle; Paul M Vink; Hans van Eenennaam; Luke A J O'Neill

doi:10.1371/journal.pone.0074103

Bruton's tyrosine kinase mediates the synergistic signalling between TLR9 and the B cell receptor by regulating calcium and calmodulin

PLoS One. 2013 Aug 14;8(8):e74103. doi: 10.1371/journal.pone.0074103. eCollection 2013.

Authors

Elaine F Kenny¹, Susan R Quinn, Sarah L Doyle, Paul M Vink, Hans van Eenennaam, Luke A J O'Neill

Affiliation

¹ Immunology Research Centre, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. kennyef@tcd.ie

Abstract

B cells signal through both the B cell receptor (BCR) which binds antigens and Toll-like receptors (TLRs) including TLR9 which recognises CpG DNA. Activation of TLR9 synergises with BCR signalling when the BCR and TLR9 co-localise within an auto-phagosome-like compartment. Here we report that Bruton's tyrosine kinase (BTK) is required for synergistic IL6 production and up-regulation of surface expression of MHC-class-II, CD69 and CD86 in primary murine and human B cells. We show that BTK is essential for co-localisation of the BCR and TLR9 within a potential auto-phagosome-like compartment in the Namalwa human B cell line. Downstream of BTK we find that calcium acting via calmodulin is required for this process. These data provide new insights into the role of BTK, an important target for autoimmune diseases, in B cell activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Agammaglobulinaemia Tyrosine Kinase
Animals
Autoimmunity
Calcium / metabolism*
Calmodulin / metabolism*
Cell Line
Humans
Inositol 1,4,5-Trisphosphate / metabolism
Interleukin-6 / biosynthesis
Mice
Mice, Inbred C57BL
Phagosomes / metabolism
Phospholipase C gamma / metabolism
Protein Transport
Protein-Tyrosine Kinases / metabolism*
Receptors, Antigen, B-Cell / metabolism*
Signal Transduction*
Toll-Like Receptor 9 / metabolism*

Substances

Calmodulin
Interleukin-6
Receptors, Antigen, B-Cell
Toll-Like Receptor 9
Inositol 1,4,5-Trisphosphate
Protein-Tyrosine Kinases
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human
Btk protein, mouse
Phospholipase C gamma
Calcium

Grants and funding

This work was funded by a grant (SFI 07/SRC/B1144-O’Neill) from Science Foundation Ireland (www.sfi.ie). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.