Nys, J.; (2010) Role of the Syk tyrosine kinase in mature B cell function. Doctoral thesis , UCL (University College London).

Abstract

Signal transduction through the antigen receptor of B cells (BCR) is crucial in controlling their development and maintenance, and is also needed for B cell immune responses. Syk, a protein tyrosine kinase, has already been implicated in signalling downstream of the BCR. Mice deficient for Syk show a developmental block at the immature to mature B cell stage such that no mature B cells are generated. Thus it has not been possible to use these targeted mice to study the role of Syk in the activation of mature B cells or in antigen-driven B cell responses. To get around this, I used mice with an inducible conditional knock out (CoKO) of Syk to generate mature B cells lacking Syk. This has allowed me to study the role of Syk in mature B cell activation and its involvement in the immune response. In this work I show that B cells from Syk CoKO mice are unable to respond to BCR stimulation. I also addressed the requirement in Syk for T-dependent immune responses, looking at both primary and secondary responses. The primary response was Syk-dependent, while, surprisingly, the secondary response seems to be Syk-independent. Finally, I investigated the role of Syk downstream of TLR receptors. Unexpectedly, Syk CoKO B cells were unresponsive to TLR4 stimulation. This defect is B cell autonomous and may be due to reduced signaling through the Akt/Gsk-3/cMyc pathway, downstream of the BCR.

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