CD22 regulates early B cell development in BOB.1/OBF.1-deficient mice

Abstract

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.

The Ets factor Spi-B is a direct critical target of the coactivator OBF-1

“…First, OBF-1 Ϫ/Ϫ B cells are impaired in BCR-triggered Ca 2ϩ mobilization; this defect was restored in CD22 Ϫ/Ϫ OBF-1 Ϫ/Ϫ double-deficient animals (48). CD22 is a negative regulator of BCR signaling, and CD22-deficient mice display a lowered activation threshold for BCR cross-linking and increased Ca 2ϩ mobilization upon BCR stimulation (49).…”

“…The crucial role of OBF-1 for the development of GCs in the spleen reflects a different mechanism, because OBF-1 Ϫ/Ϫ CD22 Ϫ/Ϫ double-deficient mice were still unable to mount humoral immune responses or to form GCs, although their BCR activation threshold was similar to the WT situation (48). The data presented here indicate that the expression of Spi-B, controlled by OBF-1 protein in the GC B cells may be a key element for the GC formation.…”

Critical Role for the Oct-2/OCA-B Partnership in Ig-Secreting Cells

“…Early reports suggested a role for both factors in processes occurring subsequent to B cell activation (10 -13, 43, 44). More recently, additional defects have been detected in OCA-B Ϫ/Ϫ mice at earlier stages of B cell development (13,45,46). Mice with Oct-2 Ϫ/Ϫ and/or OCA-B Ϫ/Ϫ B-lineage cells lack germinal centers, are deficient in the non-IgM Ig isotypes, and have significantly reduced Ig responses to T-independent and T-dependent Ags (13,44).…”

“…Mice with Oct-2 Ϫ/Ϫ and/or OCA-B Ϫ/Ϫ B-lineage cells lack germinal centers, are deficient in the non-IgM Ig isotypes, and have significantly reduced Ig responses to T-independent and T-dependent Ags (13,44). This arises in part from reduced B cell responsiveness to Ag and Th cell-induced signals (44,46,47). Given that B cells are not responding normally to these signals, few cells appear to differentiate into Ig-secreting plasmacytes.…”

Rafts and the battleships of defense: The multifaceted microdomains for positive and negative signals in immune cells

“…Activation of the transcription factor NF-B is a usual final step in signal transduction of various types of tyrosine kinases and leads transcription of apoptosis inhibitor BCL-x, BFL-1 and octamer transcription factor-2 (OCT-2) [159,160]. Similarly to mechanisms in T cells, lipid rafts are involved in the activation of NF-B by the BCR in B cells.…”