title: Role of complement receptor type 2 and endogenous complement in the humoral immune response to conjugates of complement C3d and pneumococcal serotype 14 capsular polysaccharide.
abstract: Conjugation of the complement fragment C3d to both T-cell-dependent (TD) protein and T-cell-independent type 2 (TI-2) polysaccharide antigens enhances the humoral immune response in mice immunized with either type of antigen. However, the ability of C3d-protein conjugates to enhance the antibody response in mice deficient in complement receptor types 1 and 2 (CR1 and CR2) has raised questions about the role of C3d-CR2 interactions in the adjuvant effect of C3d. In this study, we examined the role of CR2 binding and endogenous complement activation in the antibody response to conjugates of C3d and serotype 14 pneumococcal capsular polysaccharide (PPS14). To block binding of PPS14-C3d conjugates to CR2, mice were immunized with a mixture of vaccine and (CR2)2-immunoglobulin G1 (IgG1). Mice receiving (CR2)2-IgG1 at the time of primary immunization had a marked reduction in the primary anti-PPS14 antibody response but an enhanced secondary anti-PPS14 response, suggesting that C3d-CR2 interactions are required for the primary response but can have negative effects on the memory response. Further, compared with mice receiving PPS14-C3d having a high C3d/PPS14 ratio, mice immunized with PPS14-C3d with low C3d/PPS14 ratios had an enhanced secondary antibody response. Treatment of mice with cobra venom factor to deplete complement had insignificant effects on the antibody response to PPS14-C3d. Experiments with CBA/N xid mice confirmed that PPS14-C3d conjugates retain the characteristics of TI-2 rather than TD antigens. Thus, the adjuvant effect of C3d conjugated to PPS14 requires C3d-CR2 interactions, does not require activation of endogenous complement, and is not mediated by TD carrier effects.
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King, Jr. Way, Oakland, CA 94609-1673, USA.
authors.forename: Joyce K
authors.initials: JK
authors.lastname: Mitsuyoshi
authors.forename: Yong
authors.initials: Y
authors.lastname: Hu
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Test
mesh_terms: D000276:Adjuvants, Immunologic; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology*; D016667:Bacterial Capsules / Q000737:chemistry / Q000276:immunology*; D001428:Bacterial Vaccines / Q000276:immunology; D003167:Complement Activation; D015933:Complement C3d / Q000737:chemistry / Q000172:deficiency / Q000276:immunology*; D005260:Female; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007156:Immunologic Memory; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D010047:Ovalbumin / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D017464:Receptors, Complement 3d / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D017464:Receptors, Complement 3d; C056696:pneumococcal polysaccharide, type 14; D015933:Complement C3d; D010047:Ovalbumin; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse