Uncoupling CD21 and CD19 of the B-cell coreceptor

Abstract

Complement receptors (CRs) CD21 and CD35 form a coreceptor with CD19 and CD81 on murine B cells that when coligated with the B-cell receptor lowers the threshold of activation by several orders of magnitude. This intrinsic signaling role is thought to explain the impaired humoral immunity of mice bearing deficiency in CRs. However, CRs have additional roles on B cells independent of CD19, such as transport of C3-coated immune complexes and regulation of C4 and C3 convertase. To test whether association of CR with CD19 is necessary for their intrinsic activation-enhancing role, knockin mice expressing mutant receptors, Cr2 ⌬/⌬gfp , that bind C3 ligands but do not signal through CD19 were constructed. We found that uncoupling of CR and CD19 significantly diminishes survival of germinal center B cells and secondary antibody titers. However, B memory is less impaired relative to mice bearing a complete deficiency in CRs on B cells. These findings confirm the importance of interaction of CR and CD19 for coreceptor activity in humoral immunity but identify a role for CR in B-cell memory independent of CD19. In mice, complement receptors CD21 and CD35 (CRs) are encoded at the Cr2 locus by splicing of message, and they are coexpressed primarily on B cells and follicular dendritic cells (FDCs) (5, 6). CD35 and CD21 bind similar split products of C3, but in addition CD35 binds C3b and C4b. CD35 also interacts with CD19 to form a B-cell coreceptor (7). Systemic blocking of CR by antibody (8-10) or soluble receptor (11) results in impaired humoral immunity. Likewise, mice deficient in the receptors (Cr2 Ϫ/Ϫ ) bear impaired B-cell immunity to T-independent (12-14) and T-dependent Ags (15-17), infectious bacteria (18), and viruses (19,20). Studies using chimeric mice expressing CRs on either B cells (16) or FDCs (21, 22) indicate that overall humoral immunity is dependent on the presence of the receptors on both cell types. Thus, intrinsic B-cell signaling by the coreceptor and retention of Ags on FDCs are both important in B-cell immunity.Recent studies demonstrate that CR expression on B cells is important in the transport of immune complexes (ICs). Bloodborne complexes of complement-coated Ags are bound rapidly by marginal zone (MZ) B cells and are transported into the splenic follicles (12,13,23), and Ag is offloaded to FDCs (24). An analogous role for CRs on follicular B cells in peripheral lymph nodes (LNs) was identified. ICs draining via afferent lymph are trapped by subcapsular sinus (SCS) macrophages and ''transferred'' to noncognate B cells in the underlying follicular region in a CR-dependent manner (25,26). The complement-coated ICs are then transported to FDCs in a manner similar to that proposed for MZ B cells. Thus, CRs have at least two intrinsic roles on B cells: coreceptor on cognate B cells, and transport of ICs by noncognate B cells. A third, less studied role for CRs on B cells is complement regulatory activity. All mammalian cells express complement regulatory proteins (CRPs), such as Decay Activating F...

CD19+CD21low B cells and patients at risk for NIH-defined chronic graft-versus-host disease with bronchiolitis obliterans syndrome

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Complement C3-dependent uptake of targeted liposomes into human macrophages, B cells, dendritic cells, neutrophils, and MDSCs

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Do follicular dendritic cells regulate lupus-specific B cells?

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