title: Phosphatidylcholine as a metabolic cue for determining B cell fate and function.
abstract: 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 α (CCTα), 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 Cγ1wt/wt, Cγ1Cre/wtor Cγ1Cre/Crebased on Cre copy number). Serum IgG1 was markedly reduced in naïve Cγ1Cre/wtand Cγ1Cre/Cremice, while levels of IgM and other IgG subclasses were similar between Cγ1Cre/wtand Cγ1wt/wtcontrol mice. Serum IgG2b titers were notably reduced and IgG3 titers were increased in Cγ1Cre/Cremice 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 Cγ1Cre/wtand Cγ1Cre/Cremice. Correspondingly, the frequency of NP-specific IgG antibody-secreting cells was also reduced in spleens and bone marrow of Cγ1Cre/wtand Cγ. 1Cre/Cremice compared to control mice. Interestingly, though antigen-specific IgM B cells were comparable between Cγ1Cre/wt, Cγ1Cre/Creand control mice, the frequency and number of IgG1 NP-specific B cells was reduced only in Cγ1Cre/Cremice. These data indicate that PtdCho is required for the generation of both germinal center-derived B cells and antibody-secreting cells. Further, the reduction in class-switched ASC but not B cells in Cγ1Cre/wtmice suggests that ASC have a greater demand for PtdCho compared to germinal center B cells.
authors: Department of Molecular & Cellular Sciences, Liberty University College of Osteopathic Medicine, Lynchburg, VA 24502, United States.
authors: Joseph W
authors: JW
authors: Brewer
authors: Department of Microbiology & Immunology, University of South Alabama Mobile, AL 36688, United States.
authors: Viktoriya
authors: V
authors: Solodushko
authors: Department of Microbiology & Immunology, University of South Alabama Mobile, AL 36688, United States.
authors: Ileana
authors: I
authors: Aragon
authors: Department of Microbiology & Immunology, University of South Alabama Mobile, AL 36688, United States. Electronic address: rbarrington@southalabama.edu.
authors: Robert A
authors: RA
authors: Barrington
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D019916:Choline-Phosphate Cytidylyltransferase / Q000235:genetics / Q000378:metabolism*; D018858:Germinal Center / Q000473:pathology; D056724:Immunity, Humoral / Q000235:genetics; D007074:Immunoglobulin G / Q000097:blood; D007156:Immunologic Memory / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D056811:Unfolded Protein Response
chemical_list: D007074:Immunoglobulin G; D010713:Phosphatidylcholines; D019916:Choline-Phosphate Cytidylyltransferase; C500611:Pcyt1a protein, mouse
keywords: Antibody; Antibody-secreting cell; CCTα; Germinal centers; Phospholipid biosynthesis; T cell-dependent antigen; Unfolded protein response