Phosphatidylcholine as a metabolic cue for determining B cell fate and function

摘要

In activated B cells, increased production of phosphatidylcholine (PtdCho), the most abundant cellular phospholipid, is handled primarily by the CDP-choline pathway. B cell-specific deletion of CTP: phosphocholine cytidylyltransferase alpha (CCT alpha), the rate-limiting enzyme in the CDP-choline pathway, led to augmented IgM secretion and reduced IgG production, suggesting that PtdCho synthesis is required for germinal center reactions. To specifically assess whether PtdCho influences B cell fate during germinal center responses, we examined immune responses in mice whereby PtdCho synthesis is disrupted in B cells that have undergone class switch recombination to IgG1 (referred to as either C gamma 1(wt/wt), C gamma 1(Cre/wt) or C gamma 1(Cre/Cre) based on Cre copy number). Serum IgG1 was markedly reduced in naive C gamma 1(Cre/wt) and C gamma 1(Cre/Cre) mice, while levels of IgM and other IgG subclasses were similar between C gamma 1(Cre/wt) and C gamma 1(wt/wt) control mice. Serum IgG2b titers were notably reduced and IgG3 titers were increased in C gamma 1(Cre/Cre) mice compared with controls. Following immunization with T cell-dependent antigen NP-KLH, control mice generated high titer IgG anti-NP while IgG anti-NP titers were markedly reduced in both immunized C gamma 1(Cre/wt) and C gamma 1(Cre/Cre) mice. Correspondingly, the frequency of NP-specific IgG antibody-secreting cells was also reduced in spleens and bone marrow of C gamma 1(Cre/wt) and C gamma.