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 Galalpha1-3Galbeta1-4GlcNAc-R (alphaGal). Here, we examined whether conjugating antigens to the alphaGal epitope can augment their immunogenicity in alpha(1,3)galactosyltransferase knockout mice (GT0 mice) which, like humans, produce alphaGal-specific antibodies. Immunization of GT0 mice with BSA conjugated to alphaGal (alphaGal-BSA) led to significant production of anti-BSA IgG antibodies without the need for adjuvant. This response was dependent on the presence of alphaGal-reactive antibodies. Immunization of wild-type mice with alphaGal-BSA failed to induce an anti-BSA response. The presence of alphaGal-reactive antibodies also led to an increase in the T cell response to BSA following immunization with alphaGal-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 alphaGal-reactive antibodies enhanced the cytotoxic T lymphocyte anti-viral antigen response following vaccination with murine leukemia virus transformed cell lines that express alphaGal on their cell surface. Natural antibodies that bind alphaGal therefore play a key role in increasing the efficiency of priming to antigens decorated with alphaGal epitopes.