CD22 is a B cell‐specific member of the immunoglobulin superfamily and binds to sialic acid. CD22 inhibits B cell receptor signaling. Mice deficient for CD22 show a largely normal B cell development. Here, we have performed a detailed analysis of the splenic B cell population and found that the subset of marginal zone (MZ) B cells was selectively reduced in CD22‐deficient mice. CD22‐deficient mice showed a lack of TNP‐ficoll capturing cells in the MZ and a reduced response to TNP‐ficoll, particularly when the antigen was applied intravenously. CD22‐deficient B cells showed both enhanced motility as well as enhanced chemotaxis to certain chemokines. The altered chemokine responsiveness or the higher signaling capacity of CD22‐deficient B cells may lead to the compromised MZ B cell compartment, as both processes have previously been shown to affect MZ composition.

Marginal-zone (MZ) B cells represent a first line of defense against particulate blood-borne antigens. Together with the B1 cells, they are responsible for the early response against type II T-independent antigens. The molecular pathways controlling the development of MZ B cells are only poorly understood. We found that these cells are virtually absent in mice deficient in the BOB.1/OBF.1 coactivator. Loss of these B cells was demonstrated by the lack of cells showing the appropriate cell surface phenotype but also by histological analyses and tri-nitro-phenol-Ficoll capturing. The lack of these cells is a B-cell-intrinsic defect, as shown by bone marrow complementation experiments. We also show that the expression of BOB.1/OBF.1 in peripheral B cells is required for the development of MZ B lymphocytes. Our analysis of BOB.1/OBF.1-deficient splenic B cells reveals alterations in cell motility, tumor necrosis factor receptor expression, and B-cell receptor (BCR) signaling. These changes could contribute to the loss of MZ B lymphocytes by altering the maturation of the cells. Interestingly, development of and BCR signaling in B1 B cells are completely normal in BOB.1/OBF.1 mutant mice

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Mice deficient for the transcriptional coactivator BOB.1/OBF.1 show several defects in B cell differentiation. Numbers of immature transitional B cells in the bone marrow are reduced and fewer B cells reach the periphery. Furthermore, germinal center B cells are absent and marginal zone (MZ) B lymphocytes are markedly reduced. Increased levels of B cell apoptosis in these mice prompted us to analyze expression and function of antiapoptotic proteins. Bcl2 expression is strongly reduced in BOB.1/OBF.1-deficient pre–B cells. When BOB.1/OBF.1-deficient mice were crossed with Bcl2-transgenic mice, B cell development in the bone marrow and numbers of B cells in peripheral lymphoid organs were normalized. However, neither germinal center B cells nor MZ B cells were rescued. Additionally, Bcl2 did not rescue the defects in signaling and affinity maturation found in BOB.1/OBF.1-deficient mice. Interestingly, Bcl2-transgenic mice by themselves show an MZ B cell defect. Virtually no functional MZ B cells were detected in these mice. In contrast, mice deficient for Bcl2 show a relative increase in MZ B cell numbers, indicating a previously undetected function of Bcl2 for this B cell compartment.

BOB.1/OBF.1 (also called OCA‐B), a B lymphocyte‐specific transcriptional coactivator, is recruited to octamer‐containing promoters by interacting with the Oct‐1 or Oct‐2 proteins. BOB.1/OBF.1‐deficient mice show impaired secondary immunoglobulin isotype secretion and complete absence of germinal centers. Furthermore, numbers of splenic B cells are reduced due to a developmental block at the transitional B cell stage in the bone marrow. We found that surface expression of CD22 is selectively increased on B lineage cells in the bone marrow of BOB.1/OBF.1‐deficient mice. CD22 is knownas a negative regulator of B cell receptor signaling. We therefore investigated whether defects in B cell development in the BOB.1/OBF.1‐deficient mice might be due to CD22 up‐regulation. Mice weregenerated lacking both genes. In BOB.1/OBF.1×CD22 double‐deficient mice, numbers of transitional B cells in the bone marrow were normal. Consequently, double‐deficient mice also had normal B to T cell ratios in the spleen. We show that BOB.1/OBF.1–/– B cells were incapable to induce BCR‐triggered Ca2+ mobilization. This Ca2+‐signalling defect was restored in BOB.1/OBF.1×CD22 double‐deficient B cells. Nevertheless, double‐deficient animals were unable to mount humoral immune responses and to form germinal centers. Finally, we demonstrate that CD22–/– splenic B cells proliferate independently of BOB.1/OBF.1 upon stimulation with LPS. These studies suggest that the B cell differentiation defect observed in BOB.1/OBF.1–/– mice is BCR‐signal dependent. However, the impairment in germinal center formation is caused by a different mechanism.