These investigations are designed to characterize the role the immune system plays in hosts interaction with antigens in the intestinal tract. Antigen in the intestine can interact with antigen-sensitive cells in the intestine as well as alter the immune responses and the reactivity of antigen-sensitive cells in extraintestinal sites. We have demonstrated that feeding mice erythrocyte antigens resulted in a 6-fold reduction in the frequency of B cells in Peyer's patches capable of responding to the specific erythrocyte used for feeding. Feeding cells bearing major histocompatibility gene coded cell surface alloantigenic differences primed precursor cytotoxic T cells in Peyer's patches and spleen. In contrast, feeding erythrocytes specifically suppressed the ability to induce delayed-type hypersensitivity reactions (DTH) to the specific erythrocyte used for feeding. Suppression of DTH was mediated by a suppressor cell mechanism. Feeding mice erythrocyte antigens resulted also in the generation of a serum factor that specifically suppressed the induction of IgM antibody responses in vivo and in vitro to the erythrocyte used for feeding. The serum factor did not appear to be soluble antigen, anti-erythrocyte antibody or an immune complex. Oral administration of antigen may permit specific manipulation of host systemic immune responses in vivo.