The Role of T Cell Help in the Production of Antibodies Specific for Galα1–3Gal

The majority of xenoreactive natural Abs in humans recognize the carbohydrate Ag present on pig tissue, Galalpha1-3Galbeta1-4GlcNAc-R (alphaGal), synthesized by the enzyme UDP galactose:beta-D-galactosyl-1,4-N-acetyl-D-glucosaminide alpha(1-3)galactosyltransferase or alphaGT. Using alphaGT knockout mice (GT(0) mice), which like humans produce serum Abs that bind alphaGal, we examined the role of T cells in production of Abs specific for alphaGal. GT(0) mice were crossed with TCR-beta knockout mice (TCR-beta(0)) to generate double-knockout mice (GT(0)/TCR-beta(0)). While GT(0)/TCR-beta+ mice exhibited an age-dependent increase in the serum titer of natural Abs specific for alphaGal, a similar increase was not observed in GT(0)/TCR-beta(0) mice, and the titer of alphaGal-specific Abs in double knockouts was significantly lower than in age-matched GT(0)/TCR-beta+ mice. Immunization with pig cells resulted in a significant increase in the serum titer of alphaGal-specific Abs in GT(0)/TCR-beta+ mice, but had no effect on the level of alphaGal-specific serum Abs in GT(0)/TCR-beta(0) mice. Treatment of GT(0)/TCR-beta+ mice with anti-CD40L Abs before immunization with pig cells prevented sensitization to alphaGal. Our data suggest that the majority of alphaGal-specific Abs are T cell dependent and that production of alphaGal-specific Abs after sensitization can be prevented by blocking costimulatory pathways.