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Complement Component C3d-Antigen Complexes Can Either Augment or Inhibit B Lymphocyte Activation and Humoral Immunity in Mice Depending on the Degree of CD21/CD19 Complex Engagement¹

Youngkyun Lee^2,*, Karen M. Haas^2,*, Dennis O. Gor^3,, Xuedong Ding, David R. Karp, Neil S. Greenspan, Jonathan C. Poe^* and Thomas F. Tedder^4,*

^* Department of Immunology, Duke University Medical Center, Durham, NC 27710; Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106; and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390

C3d can function as a molecular adjuvant by binding CD21 and thereby enhancing B cell activation and humoral immune responses. However, recent studies suggest both positive and negative roles for C3d and the CD19/CD21 signaling complex in regulating humoral immunity. To address whether signaling through the CD19/CD21 complex can negatively regulate B cell function when engaged by physiological ligands, diphtheria toxin (DT)-C3d fusion protein and C3dg-streptavidin (SA) complexes were used to assess the role of CD21 during BCR-induced activation and in vivo immune responses. Immunization of mice with DT-C3d₃ significantly reduced DT-specific Ab responses independently of CD21 expression or signaling. By contrast, SA-C3dg tetramers dramatically enhanced anti-SA responses when used at low doses, whereas 10-fold higher doses did not augment immune responses, except in CD21/35-deficient mice. Likewise, SA-C3dg (1 µg/ml) dramatically enhanced BCR-induced intracellular calcium concentration ([Ca²⁺]_i) responses in vitro, but had no effect or inhibited [Ca²⁺]_i responses when used at 10- to 50-fold higher concentrations. SA-C3dg enhancement of BCR-induced [Ca²⁺]_i responses required CD21 and CD19 expression and resulted in significantly enhanced CD19 and Lyn phosphorylation, with enhanced Lyn/CD19 associations. BCR-induced CD22 phosphorylation and Src homology 2 domain-containing protein tyrosine phosphatase-1/CD22 associations were also reduced, suggesting abrogation of negative regulatory signaling. By contrast, CD19/CD21 ligation using higher concentrations of SA-C3dg significantly inhibited BCR-induced [Ca²⁺]_i responses and inhibited CD19, Lyn, CD22, and Syk phosphorylation. Therefore, C3d may enhance or inhibit Ag-specific humoral immune responses through both CD21-dependent and -independent mechanisms depending on the concentration and nature of the Ag-C3d complexes.

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