The role of T cell help in the production of antibodies specific for Gal alpha 1-3Gal.
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.
Cretin
Nathalie
N
Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, USA.
Bracy
Jennifer
J
Hanson
Krista
K
Iacomini
John
J
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000910:Antibodies, Heterophile / Q000096:biosynthesis*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000918:Antibody Specificity / Q000235:genetics; D000955:Antigens, T-Independent / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007114:Immunization; D007274:Injections, Intraperitoneal; D007963:Leukocytes, Mononuclear / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013552:Swine; D013556:Swine, Miniature; D006377:T-Lymphocytes, Helper-Inducer / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism
D019138:Antibodies, Blocking; D000910:Antibodies, Heterophile; D000911:Antibodies, Monoclonal; D000955:Antigens, T-Independent; D016693:Receptors, Antigen, T-Cell, alpha-beta; D023201:CD40 Ligand; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase