Studies on the mechanisms of the maturation of germinal center B cells.

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In a T-cell dependent immune response, antigen-activated B cells switch their IgH chain expression and hypermutate their VH and VL regions to improve the affinity of its antibodies. This maturation processes are believed to occur in the germinal center. To understand the role of the germinal center for B cell maturation and cellular interactions in germinal centers, we carried out immunohistochemical and functional analysis of germinal center B cell.(1) We found that some of germinal center B cells in light zone, marginal zone and mantle zone express CD38. IL-5Ralpha positive B cells were localized in light zone and some of them appear to co-express CD38.(2) IL-4 and IL-5 in the presence of anti-CD40 mAb induced semi-purified GB B cells to differentiate into antigen specific IgG1 antibody-secreting cells. FACS analysis revealed that stimulation of semi-purified GB B cells with IL-4 and anti-CD40 mAb enhanced expression of IL-5Ralpha.(3) CD38 ligation on B cells induced proliferation, IgM secretion, and tyrosine phosphorylation of Bruton's tyrosine kinase (Btk) in B cells from wild-type mice but not in B cells from XID mice. CD38 ligation can cynergistically acts with IL-5 to enhance B-cell proliferation, Blimp-1 gene expression, and IgM production. Flow cytometry analysis revealed that CD38 ligation enhanced the expression of the IL-5Ralpha on B cells.(4) Mutational analysis using substitution mutants of IL-5Ralpha revealed that one of the proline residues, particularly Pro352 or Pro355, in the membrane proximal proline-rich sequence (Pro352-Pro353-X-Pro355) of the cytoplasmic domain of IL-5Ralpha is required for cell proliferation and for activation of JAKs/STAT5 pathway.