Immunoglobulin E responses to known environmental antigens (allergens) may serve as a general model to investigate germline genetic restriction of the immune response. We have previously shown genetic linkage between IgE responses to major allergens and the T-cell receptor (TCR) A/D locus, but not to TCR-B, implying that elements in TCR A/D restrict the ability to react to specific antigens. We now show, in two sets of subjects from the same population, a strong allelic association between a VA8.1 polymorphism (VA8.1(*)2) and reactivity to Der p II, a major antigenic component of the house dust mite Dermatophagoides pteronyssinus. Association was also seen between Der p II IgE titres and HLA-DRB1(*)1501 alleles. Reactivity to Der p II was confined to subjects who were positive for VA8.1(*)2 and HLA-DRB1(*)1501, demonstrating germline HLA-DR and TCR-A interaction in restricting the response to exogenous antigen.