We have examined the role of Ts cels and APC in regulating the tolerance of systemic DTH in mice fed OVA. Oral tolerance to OVA was prevented by eliminating Ts with dGuo and by treating mice with anti-I-J antiserum. In addition, activating the reticuloendothelial system (RES) with oestradiol, muramyl dipeptide (MDP) or GvHR prevented the induction of tolerance. Further studies showed that prevention of oral tolerance correlated with the ability to enhance APC activity and that oestradiol also abrogated the induction of Ts after feeding OVA. Our results show that the tolerance of systemic DTH in mice fed OVA reflects complex interactions between APC and Ts and suggest that defects in these regulatory events may be responsible for clinical food sensitive enteropathy.