The normal human diet contains Targe amounts of protein antigens. These antigens can be detected in sera in nanogram quantities for several hours after a meal. However, proliferation of human T cells stimulated with common food antigens is usually weak and antibody levels in sera are low, consistent with a state of unresponsiveness. We focused on two mechanisms of oral tolerance: anergy and suppression. We tested whether antigen-specific proliferation to common food antigens, ovalbumin (OVA) and bovine gamma globulin (BGG), can be restored by exogenous IL-2 suggesting anergy, and whether antigen-specific proliferation to immunogens such as purified protein derivative from M. tuberculosis (PPD) or tetanus toxoid (TT) can be inhibited by addition of food antigens to cell cultures in vitro suggesting suppression. Keyhole limpet hemocyanin (KLH), an antigen which is not a part of human diet, served as a negative control. T lymphocytes from 5 volunteers were cultured with antigens (OVA, BGG, KLH) and autologous antigen-presenting cells with or without rhIL-2. A significant increase in proliferation to both food antigens (OVA, BGG) was detected when exogenous IL-2 was added to the culture compared to the proliferation of T cells cultured with KLH plus IL-2. No differences in proliferation between KLH and the medium control were observed in any culture. Significant inhibition of proliferation to TT or PPD was detected for OVA in 2 cases and for BGG in 6 cases out of 12 volunteers tested on multiple occasions. Our data suggests that both mechanisms, anergy and suppression, can be involved in the maintenance of oral tolerance to food antigens. This observation does not exclude the possibility that clonal deletion is also involved.