UC San Diego

Atherosclerosis is hallmarked by hypercholesterolemia but its progression is greatly modulated by the immune system. B cells, which are responsible for antibody secretion, have been shown to positively or negatively affect atherogenesis (chapter 5 details various collaborative studies assessing the role of B-cells in various models of atherosclerosis). B-1 cells, which are innate-like B cells have often been shown to inhibit atherosclerosis progression through secretion of natural antibodies while adaptive B-2 cells have demonstrated protective or injurious properties. B-1 and B-2 cells differ markedly in ontogenic, genetic, and phenotypic properties. While B-2 cell regulation has been extensively studied, the regulation of B-1 cells remains relatively mysterious. The overarching theme of this dissertation is to understand the transcriptional mechanisms that govern the unique properties of B-1 cells. Members of the nuclear receptor superfamily of transcription factors regulate important processes in many immune cells. However the expression and function of nuclear receptors in B-1 cells was entirely unknown. I hypothesized that members of the nuclear receptor superfamily would be expressed in and regulate important innate immune functions of B-1 cells, such as survival, proliferation, and secretion of natural antibodies. Nuclear receptor expression was compared between B-1 and B-2 cells. The function of the mineralocorticoid, glucocorticoid, and liver x receptors, which were expressed in B-1 cells, was analyzed ex vivo. No significant effect of mineralocorticoid receptor activation or antagonism was found in B-1 cells. LXR activation inhibited B-1 cell proliferation. Glucocorticoid receptor activation inhibited antibody production and potently induced apoptosis in B-1 cells. The effect of dexamethasone, a synthetic glucocorticoid, upon the transcriptome B-1 and B-2 cells was compared. Surprisingly different sets of genes were regulated by dexamethasone in B-1 and B-2 cells. An analysis of the cistrome of GR was performed to test if the glucocorticoid receptor has unique genome-wide binding patterns between B -1 and B-2 cells. The GR cistrome was remarkably different between B-1 and B-2 cells. The unique binding of GR in B-1 and B-2 cells associated with cell-type specific enhancers. Future studies endeavor to identify cell-type specific lineage determining factors that control enhancer formation is B-1 versus B-2 cells