Immunoglobulin-mediated signal transduction in B cells from CD45-deficient mice.

Abstract

SummaryCD45 expression is essential for immunoglobulin (Ig)-mediated B cell activation. Treatments with either anti-Ig or anti-CD45 suggest that CD45 may facilitate early signaling events such as calcium mobilization, and phosphoinositide hydrolyis as well as later events leading to transcription of genes such as c-myc. To examine the role of CD45 more extensively, CD45-deficient mice were generated by disruption of exon 6. Although normal numbers of B cells were found in peripheral lymphoid tissues, CD45-deficient cells failed to proliferate upon IgM crosslinking. In the present study, we demonstrate that the fraction of high buoyant density B cells is reduced while low buoyant density cells are increased. Moreover, there is a significant decline in the number of splenic B cells of the mature lgD hi, IgM I~ phenotype. Although both the basal and anti-Ig-induced levels of phosphorylation of Ig-0t and phospholipase C',/2 are indistinguishable from that observed in CD45 + control B cells, a major distinction was found in Ca 2+ mobilization. While anti-Ig-induced mobilization of intracellular Ca 2+ stores was normal, influx from extracellular sources was abrogated. This finding reveals a novel pathway of regulating B cell responses mediated by CD45. Evidence from a variety of sources clearly demonstrates that the expression of CD45 is essential for activation of B lymphocytes after cross-linking of the B cell receptor (BCR) (1-6). In vitro activation studies using primary cells treated with either anti-Ig or anti-CD45 suggest that CD45 facilitates early signaling events such as calcium mobilization (6), and phosphoinositide hydrolyis as well as later events leading to transcription of genes such as c-myc (7). Cell lines have also been used to examine the role of CD45. In some cases conflicting results have emerged from such studies. For example, it was demonstrated that the plasmacytoma J558LIxm3, which lacks CD45, failed to mobilize Ca 2+ after BCR cross-linking. This effect was restored in J558LF~m3 cells by transfection with a eDNA encoding CD45 (1). In contrast, CD45-variants of the CD45 + immature cell line WEHI231, had a slightly delayed but increased and prolonged Ca 2+ response upon BCR cross-linking (8). Whether this discrepancy accurately reflects the different maturation states of these cell lines, or is due to abnormalities peculiar to transformed cells, remains to be determined.To examine the role of CD45 more extensively, CD45-deficient mice were generated by disruption of exon 6 (9). Mice homozygous for the CD45 exon 6 mutation lacked CD45 expression on B cells and on the majority of thymocytes and peripheral T cells. A block in T cell development occurred at the transition from immature CD4+CD8 + double-positive to mature single-positive thymocytes resulting in a significant reduction in peripheral T cells. Residual peripheral T cells exhibited impaired anti-CD3 and anti-TCR signaling. In contrast to the paucity of peripheral T cells, approximately normal numbers of B cells were found in peripheral ...

B Cell Positive Selection by Soluble Self-Antigen

“…Not only is the BCR itself mandatory, but the BCR signaling pathway is also necessary, because many mutations affecting this pathway are known to interfere with B cell maturation (15,18,(31)(32)(33)(34). Besides the indirect arguments mentioned earlier, the direct evidence that a self-Ag can be involved in B cell development comes from Hayakawa et al (14).…”

Lupus IgG VH4.34 Antibodies Bind to a 220-kDa Glycoform of CD45/B220 on the Surface of Human B Lymphocytes

“…Naive lymphopenia could be induced by V H 4.34 Abs whether through their reported lymphocytotoxic activity or by alternative mechanisms (38,60). Thus, while costimulatory signaling through the Ag receptor and CD45, in particular B220, is essential both for B cell activation and proliferation, ligation of CD45 alone promotes apoptosis of both T and B lymphocytes (61)(62)(63)(64). Therefore, V H 4.34 Abs could induce apoptosis of virgin naive B cells upon ligation of CD45 alone while promoting activation and expansion of autoreactive naive B cells actively costimulated by self Ag through the B cell receptor.…”

An extracatalytic function of CD45 in B cells is mediated by CD22

“…S3B) (11,40). FO-II and -I have both been described as long-lived (and therefore "mature") splenic B-cell populations, but FO-I does not develop in the absence of antigen or in Btkdeficient mice with impaired BCR signaling (41,42).…”