Responses of B lymphocytes to various ligands, including antigens, are associated with the activation of serinethreonine specific protein kinases of protein kinase C family. Activation of distinct protein kinase C isoforms was found to be specifically associated with proliferation, differentiation or programmed death of lymphocytes. We have been involved in studies of the physiological significance of individual PKCs by generating mice deficient for PKCbetaI/II isoforms and showing the essential role of PKCbetaI/II in B cell responses to antigenic stimulation in vitro and in vivo. Recently we generated mice deficient for PKCdelta and found signs of defective B cell tolerance induction in these mice. The overall goal of the experiments described in this application is to address the mechanism of PKCdelta involvement in B cell signaling and its role in regulation of B cell responses to self-antigens.
Our first aim i s to address the role of PKCdelta in B cell signaling by studying expression, activity, intracellular localization and tyrosine phosphorylation of PKCdelta in resting and activated B lymphocytes.
Our second aim i s to investigate the consequences of PKCdelta deficiency for B cell activation in vitro and in vivo.
The third aim describes our plan to study selection of PKCdelta -/- B cells expressing transgenic BCR that recognizes hen egg lysozyme (HEL). By studying phenotype and signaling properties of the PKCdelta -/- B IgHEL B cells which develop in the absence or presence of soluble HEL, we plan to identify mechanisms of PKCdelta involvement in B cell anergy induction. We plan to extend our studies on the role of PKCdelta in B cell tolerance by studying development and function of the PKCdelta -/- B cells expressing transgenic BCRs specific for double- or single-stranded DNA. Finally, we will address the possible changes in expression and/or activity of PKCdelta in B cells of mice genetically predisposed to the development of B cell mediated autoimmunity. Collectively we hope that these studies will shed further light into the regulation of signal transduction in B cells and provide data that will be useful in the treatment of disease related to immune dysfunction.
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