B-1 cells constitute a unique population of B cells, with numerous distinguishing phenotypic, transcriptomic,and functional characteristics. B-1 cells differ from conventional B-2 cells in the rules that govern stimulatedcell cycle responses and in the unstimulated, spontaneous secretion of non-immune immunoglobulin. Thelong term objectives of the proposed work are twofold: 1) to elucidate pdmary characteristics that dictate theunique nature of B-1 cells; 2) to identify key mediators that specify proliferative responses in, anddifferentiative features of, B-1 cells. The proposed studies build on a longstanding collaboration between thetwo project leaders that has already produced new insights regarding previously unrecognized restrictionpoints regulating cell cycle progression in B cells. The proposed study will exploit these advances to furtherprobe the nature of cell cycle regulation, and at the same time take advantage of the proven complimentaryexpertise of the investigators, and recent key findings, to extend this work to elucidate the determinants ofimmunoglobulin secretion. Several molecular approaches will be utilized to address the function of cyclinD3-cdk4 complexes in B cells (Project 1) and relationship between Bcl-6 and immunoglobulin secretion, and!the role of the peritoneal environment, in B-1 cells (Project 2). These studies will generate new informationregarding the underlying nature of B-1 cells, and will identify means to manipulate B cell clonai expansionand spontaneous immunoglobulin secretion to improve resistance to infection and/or intoxication by naturalmicroorganisms or bioterrodsm agents, and to forestall and/or treat autoimmune disease.
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