Journal
JOURNAL OF IMMUNOLOGY
Volume 175, Issue 5, Pages 2859-2867Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.175.5.2859
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- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [Z01AI000898, R21AI040181, R01AI039246, R01AI040181] Funding Source: NIH RePORTER
- NIAID NIH HHS [AI40181, AI39246] Funding Source: Medline
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The adaptive immune response is tightly regulated to limit responding cells in an Ag-specific manner. On B cells, coreceptors CD21/CD19 modulate the strength of BCR signals, potentially influencing cell fate. The importance of the CD95 pathway was examined in response of B cells to moderate affinity Ag using an adoptive transfer model of lysozyme-specific Ig transgenic (HEL immunoglobulin transgene (MD4) strain) B cells. Although adoptively transferred Cr2(+/+) MD4 B cells are activated and persist within splenic follicles of duck egg lysozyme-immunized mice, Cr2(-/-) MD4 B cells do not. In contrast, Cr2(-/-) MD4 lpr B cells persist after transfer, suggesting that lack of CD21/CD35 signaling results in CD95-mediated elimination. Cr2 deficiency did not affect CD95 levels, but cellular FLIP (c-FLIP) protein and mRNA levels were reduced 2-fold compared with levels in Cr2(+/+) MD4 B cells. In vitro culture with Cr2(+/+) MD4 B cells demonstrated that equimolar amounts of rHEL-C3d(3) were more effective than hen egg lysozyme alone in up-regulating c-FLIP levels and for protection against CD95-mediated apoptosis. Collectively, this study implies a mechanism for regulating B cell survival in vivo whereby the strength of BCR signaling (including coreceptor) determines c-FLIP levels and protection from CD95-induced death.
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