The influence of natural antibody specificity on antigen immunogenicity

The natural antibody repertoire in humans, apes and Old World primates is distinct from the repertoire of all other placental mammals, and encodes antibodies specific for the carbohydrate epitope Gal alpha 1-3 Gal beta 1-4GlcNAc-R (alpha Gal). Here, we examined whether conjugating antigens to the alpha Gal epitope can augment their immunogenicity in alpha(1,3)galactosyltransferase knockout mice (GT(o) mice) which, like humans, produce alpha Gal-specific antibodies. Immunization of GT(o) mice with BSA conjugated to alpha Gal (alpha GalBSA) led to significant production of anti-BSA IgG antibodies without the need for adjuvant. This response was dependent on the presence of alpha Gal-reactive antibodies. Immunization of wild-type mice with alpha Gal-BSA failed to induce an anti-BSA response. The presence of aGal-reactive antibodies also led to an increase in the T cell response to BSA following immunization with alpha Gal-BSA when compared with mice that received BSA alone, resulting in an increased frequency of IFN-gamma- and IL-4-producing BSA-specific T cells. In addition, the ability to produce alpha Gal-reactive antibodies enhanced the cytotoxic T lymphocyte anti-viral antigen response following vaccination with murine leukemia virus transformed cell lines that express alpha Gal on their cell surface. Natural antibodies that bind alpha Gal therefore play a key role in increasing the efficiency of priming to antigens decorated with alpha Gal epitopes.