Impaired intracellular calcium mobilization and NFATc1 availability in tolerant anti-insulin B cells.

Acevedo-Suárez CA, Kilkenny DM, Reich MB, Thomas JW
J Immunol. 2006 177 (4): 2234-41

PMID: 16887983 · DOI:10.4049/jimmunol.177.4.2234

B lymphocytes that recognize soluble self-Ags are routinely found in normal individuals in a functionally inactive or anergic state. Current models indicate that this tolerant state is maintained by interactions with self-Ags that uncouple the BCR from downstream signaling pathways and increase levels of free calcium. Contrary to this expectation, B cells that harbor anti-insulin Ig transgenes (125Tg) are maintained in a tolerant state even though free calcium levels remain normal and tyrosine kinase substrate phosphorylation is preserved following BCR stimulation. Under basal conditions, intracellular levels of inositol 1,4,5-trisphosphate are increased and NFATc1 levels are reduced in 125Tg B cells. The 125Tg B cells are markedly impaired in their ability to mobilize calcium upon stimulation with ionomycin, and BCR-induced calcium mobilization from internal stores is decreased. In contrast, poisoning intracellular calcium pumps with thapsigargin increases calcium mobilization in 125Tg B cells. Changes in calcium signaling are accompanied by a failure of 125Tg B cells to translocate NFATc1 into the nucleus following stimulation with either anti-IgM or ionomycin. Thus, disassociation of BCR from multiple signaling pathways is not essential for maintaining tolerance in anti-insulin 125Tg B cells. Rather, BCRs that are occupied by autologous insulin deliver signals that induce changes in intracellular calcium mobilization and maintain tolerance by preventing activation of key transcription factors such as NFAT.

MeSH Terms (12)

Animals B-Lymphocyte Subsets Calcium Calcium Signaling Cells, Cultured Immune Tolerance Immunoglobulin M Insulin Mice Mice, Inbred C57BL Mice, Transgenic NFATC Transcription Factors

Connections (3)

This publication is referenced by other Labnodes entities:

Links