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Published on: March 6, 2010
Immunoglobulin-mediated signal transduction in B cells from CD45-deficient mice
T Benatar1, R Carsetti, C Furlonger
1Wellesley Hospital Research Institute, University of Toronto, Canada.
Insights
CD45 protein is crucial for B cell activation. CD45-deficient B cells show impaired calcium influx, revealing a new regulatory pathway for B cell responses.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- CD45 protein tyrosine phosphatase is vital for immunoglobulin (Ig)-mediated B cell activation.
- Previous studies suggest CD45 facilitates early signaling events like calcium mobilization and later gene transcription.
Purpose of the Study:
- To investigate the role of CD45 in B cell activation using CD45-deficient mice.
- To elucidate the specific signaling defects in B cells lacking CD45.
Main Methods:
- Generation of CD45-deficient mice by disrupting exon 6.
- Analysis of B cell populations, including density and phenotype (IgDhi, IgMlo).
- Assessment of calcium (Ca2+) mobilization and protein phosphorylation (Ig-alpha, phospholipase C gamma 2) upon anti-Ig stimulation.
Main Results:
- CD45-deficient mice had normal B cell numbers but failed to proliferate upon IgM crosslinking.
- Reduced high buoyant density B cells and increased low buoyant density B cells were observed.
- While intracellular calcium release was normal, extracellular calcium influx was abrogated in CD45-deficient B cells.
- Phosphorylation of Ig-alpha and phospholipase C gamma 2 remained unaffected.
Conclusions:
- CD45 plays a critical role in regulating extracellular calcium influx essential for B cell activation.
- This study uncovers a novel CD45-mediated pathway in controlling B cell responses.
Abstract:
CD45 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 IgDhi, IgMlo phenotype. Although both the basal and anti-Ig-induced levels of phosphorylation of Ig-alpha and phospholipase C gamma 2 are indistinguishable from that observed in CD45+ control B cells, a major distinction was found in Ca2+ mobilization. While anti-Ig-induced mobilization of intracellular Ca2+ stores was normal, influx from extracellular sources was abrogated. This finding reveals a novel pathway of regulating B cell responses mediated by CD45.
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