REGULATION OF CR2/CD21 EXPRESSION AND ACTIVATION

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DESCRIPTION (Applicant's Abstract): The murine CD21/Cr2 gene encodes two proteins demonstrated to be critical in the acquisition of an optimal immune response. Long considered as a phagocytic receptor for Complement-bearing immune complexes, the CD21 pathway now includes signals for B-cell survival and optimal activation, and presentation of native antigen by follicular dendritic cells (FDC) in the germinal centers of the spleen. The expression of murine CD21 is tightly controlled. The proteins are only found on B-cells during a specific stage of differentiation, and are expressed by FDC once these cells have taken up their position within the spleen. This competing application proposes to continue the laboratories analysis of the mechanism of CD21 gene control, and to initiate a new project to dissect the transcriptional pathways that are activated (or inactivated) upon receptor ligation. We propose that the transcription of the CD21 gene is regulated by a set of transcription factors that are present in all lymphocytes and that the lack of expression by T-cells is due to either (1) the presence of a site specific, T-cell specific histone deacetylase, or (2) a site specific, B-cell specific histone acetylase. Published and preliminary data supports DNA accessibility as a primary determinant of CD21 expression in lymphocytes. In vivohomologous recombination experiments are proposed to dissect the role of key regulatory sites in the control of CD21 expression during B-cell differentiation and by FDC. The second major hypothesis to be tested is that B-cell activation via CD21 ligation, plus or minus surface Ig activation, leads to a pathway of transcriptional control that directly influences the state of B-cell differentiation and activation. Using novel gene analysis approaches, we propose to fully characterize these transcriptional pathways for the expression (depression) of known and novel genes. Elucidation of these pathways will lead to means by such activation can be minimized when inappropriate, or accentuated when required for the generation of an optimal B-cell response.