ABSTRACT
The positive and negative selection of antigen-reactive B cells take place in the germinal center (GC) during an immune responses. However, the precise molecular mechanisms underlying these selection machineries, including the involvement of antigen receptor signaling molecules, remain to be elucidated. We found that expression levels of Igα and Igß, which are the essential components of B cell antigen-receptor complex, were differentially regulated in GC B cells and that the expression of Igß was more prominently down-regulated in a portion of GC B cells. The suppression of Igß down-regulation reduced the number of GL7(+)GC B cells and the affinity maturation in T-dependent responses was markedly impaired. In addition, the disease phenotypes in autoimmune-prone mice were ameliorated by blocking of Igß down-regulation. These results suggest that Igß down-regulation is involved in the normal positive selection in GC and the accumulation of autoreactive B cells in autoimmune-prone mice.
Subject(s)
B-Lymphocytes/immunology , B-Lymphocytes/metabolism , CD79 Antigens/metabolism , Germinal Center/immunology , Germinal Center/metabolism , Animals , Antibody Formation , Autoimmunity , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , CD79 Antigens/genetics , Cell Membrane/metabolism , Down-Regulation , Gene Expression Regulation , Immunoglobulin Class Switching , Interleukins/metabolism , Mice , Somatic Hypermutation, ImmunoglobulinABSTRACT
It has been shown that cytoplasmic tail of the IgG1 B cell receptors (BCRs) are essential for the induction of T-dependent immune responses. Also it has been revealed that unique tyrosine residue in the cytoplasmic tail of IgG2a has the potential of being phosphorylated at tyrosine and that this phosphorylation modulates BCR signaling. However, it still remains unclear whether such phosphorylation of IgG cytoplasmic tail is involved in the regulation of BCR surface expression. In order to approach the issue, we established and analyzed the cell lines which express wild-type or mutated forms of IgG1 BCR. As the result, we found that IgG1 BCR expressed normally on the surface of A20 B cell line independent of the cytoplasmic tail. In contrast, IgG1 BCR whose cytoplasmic tyrosine was replaced with glutamic acid which mimics phosphorylated tyrosine, was expressed most efficiently on the surface of non-B lineage cells and Igß-down-regulated B cell lines. These results suggest that tyrosine residue in IgG cytoplasmic tail is playing a essential role for the efficient expression of IgG BCR on the cell surface when BCR associated signaling molecules, including Igß, are down-regulated.