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Role of CCTα in B‐lymphocyte Development from Hematopoietic Stem Cell to Plasma Cell
Author(s) -
Fagone Paolo,
Jackowski Suzanne
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.643.9
Subject(s) - b cell , b 1 cell , biology , plasma cell , haematopoiesis , bone marrow , cd40 , spleen , microbiology and biotechnology , stem cell , immunoglobulin m , antibody , t cell , immunology , immunoglobulin g , antigen presenting cell , immune system , in vitro , cytotoxic t cell , biochemistry
B‐lymphocytes, or B‐cells, originate in the bone marrow and mature in the spleen and lymph nodes. Upon activation with ligand, mature B‐cells proliferate and differentiate either into memory B‐cells or immunoglobulin (Ig)‐secreting plasma cells. Plasma cells are distinct from mature or memory B‐cells and possess a more extensive endoplasmic reticulum (ER) and Golgi compartment to sustain high‐capacity Ig synthesis and secretion. Phosphatidylcholine (PtdCho) is the major lipid component of B‐cell membranes and the CDP‐choline pathway is the major source of PtdCho during B‐cell differentiation after LPS stimulation. Choline cytidylyltransferase (CCT) activity regulates the rate of PtdCho synthesis through the CDP‐choline pathway in B‐cells. Mice were derived which lacked B‐cell expression of CCTα the predominant isoform, to define the role(s) of this protein in B‐cell development and function. Knockout (KO) and wild‐type (WT) mice showed no difference in spleen structure or the total number of splenic B‐cells as determined by immunohistochemistry and flow cytometry. However, KO mice lacked the subpopulation of marginal zone B‐cells and had lower basal serum IgG levels, whereas IgM levels were comparable to genetically matched WT mice. Immunization with a T‐cell dependent antigen in vivo should elicit an IgG response, but KO mice were unable to switch from IgM to IgG production and had elevated levels of IgM. B‐cells lacking CCTα expression had intact signaling responses to stimulation of the B‐cell receptor with anti‐IgM, but were unable to synthesize DNA or proliferate following stimulation with LPS or anti‐IgM in vitro, in contrast to WT cells. Our working model proposes that the requirement for PtdCho synthesis for the combined tasks of proliferation, clonal expansion and ER biogenesis cannot be met by the reduced CCT activity in the KO B‐cells. (Supported by NIH GM45737 and ALSAC.)