CTP:Phosphocholine Cytidylyltransferase α Is Required for B-cell Proliferation and Class Switch Recombination

Abstract

CTP:phosphocholine cytidylyltransferase (CCT) is a key ratecontrolling enzyme in the biosynthetic pathway leading to the principle membrane phospholipid, phosphatidylcholine. CCT is the predominant isoform expressed in mammalian cells. To investigate the role of CCT in the development and function of B-lymphocytes, mice with B-lymphocytes that selectively lacked CCT were derived using the CD19-driven Cre/loxP system. When challenged with a T-cell-dependent antigen, the animals harboring CCT-deficient B-cells exhibited a hyper-IgM secretion phenotype coupled with a lack of IgG production. The inability of CCT / B-cells to undergo class switch recombination correlated with a proliferation defect in vivo and in vitro in response to antigenic and mitogenic stimuli. Lipopolysaccharide stimulation of CCT / B-cells resulted in an early trigger of the unfolded protein response-mediated splicing of Xbp-1 mRNA, and this was accompanied by accelerated kinetics of IgM secretion and higher incidence of IgM-secreting cells. Thus, the inability of stimulated B-cells to produce enough phosphatidylcholine prevents proliferation and class switch recombination but leads to unfolded protein response activation and a hyper-IgM secretion phenotype.