The role of CD46 in human Th1 induction and contraction (DNA packaging, gene expression, regulation of cell metabolism)
The intracellular domains of CD46 (termed CYT-1 and CYT-2) are cleaved by the γ-secretase complex upon autocrine activation and translocate to the nucleus. This is a required event for CD46-driven increase in glycolysis and IFN-γ secretion and Th1 induction in human CD4+ T cells. How exactly CYT-1 and CYT-2 regulate genes is currently unclear. We have generated antibodies to CYT-1 and CYT-2, performed ChIP-seq experiments in CD4+ T cells and generated a list of direct CD46 target genes. Pathways analysis revealed that the large majority of CD46 target genes are falling into the ‚nucleosome and metabolism regulation’ pathways – critically supporting our notion that intracellular/autocrine complement regulates basic cell physiology. We are currently defining the exact mechanisms as to how CD46 regulates DANN packaging etc.