COMPLEMENT AND ANTIBODY REGULATION OF T CELL INDEPENDENT ANTIBODY RESPONSES

Abstract

Antibody responses to carbohydrate antigens are critical for protection against many different parasites, fungi, bacteria, infectious diseases, and types of cancers. Carbohydrate antigens are composed of repetitive monomers and are often classified as Thymus independent type 2 antigens (TI-2 Ags) due to their ability to induce antibody responses in the absence of cognate T cell help. Impaired recall responses to TI-2 Ags is a major hurdle that prevents booster immunizations with TI-2 Ags. This may be due to the antigen specific-antibody antigen immune complexes generated during secondary immunization. These complexes are expected to activate complement and engage Fc receptors. We therefore investigated the role of complement and Fc receptor signaling in suppressed antibody responses to TI-2 Ags. We used transgenic and knockout mice in conjunction with antigen-specific monoclonal antibodies to measure complement and Fc gamma receptor-dependent alterations in antigen-specific B-cell antibody production in vivo. Our data show an important role for the complement protein C4 but not Fc gamma receptor I, III, or IV in mediating suppression of antibody production to TI-2 Ag when antigen specific IgM, and IgG1, and/or IgG3 is present. Understanding the mechanisms enabling antigen specific antibody to suppress antibody responses to TI-2 antigens is important in that it can provide new targets for vaccine design, or allow for manipulation of pre-existing vaccines that will increase efficacy.