We used γδ TCR-deficient (TCRδ(-/-)) mice to examine the role of γδ T cells for induction of mucosal responses and systemic tolerance to high versus low doses of oral antigen. When either TCRδ(-/-) or TCRδ(+/+) mice were immunized orally with a high dose of ovalbumin (OVA) prior to parenteral challenge, systemic IgG and IgE antibody responses were markedly reduced in both types of mice, while mucosal IgA responses were reduced only in the TCRδ(-/-) mice. Reduced T cell proliferative responses and delayed-type hypersensitivity were seen in TCRδ(-/-) and TCRδ(+/+) mice given the high dose of OVA. Antigen-induced T(h)1 and T(h)2 cytokine production by splenic CD4+ T cells was severely inhibited in orally tolerized TCRδ(-/-) and TCRδ(+/+) mice. In contrast, while oral tolerance associated with increased levels of IL-10 synthesis was induced by a low dose of OVA in TCRδ(+/+) mice, the TCRδ(-/-) mice were not tolerized and failed to produce IL-10. Our findings indicate that γδ T cells play a significant immunoregulatory role in IL-10-mediated, low-dose oral tolerance induction, but are not essential participants in the induction of systemic tolerance to orally introduced antigens given in larger doses.