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CD21/CD19 Coreceptor Signaling Promotes B Cell Survival during Primary Immune Responses¹

Robert A. Barrington^*, Ming Zhang^2,*, Xuemei Zhong^2,, Helena Jonsson^*, Nichol Holodick, Anu Cherukuri, Susan K. Pierce, Thomas L. Rothstein and Michael C. Carroll^3,*

^* CBR Institute for Biomedical Research and Department of Pathology, Harvard University, Boston, MA 02115; Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and Department of Immunobiology, Boston University Medical Center, Boston, MA 02118

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-C3d₃ 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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