To understand how orally introduced antigen regulates peripheral immune responses, we fed cytochrome c protein to mice transgenic for the β chain of a cytochrome c–specific TCR and followed the antigen-specific T cell responses with a cyt c/I-E^k tetramer staining reagent. We find that within 6 hr of cytochrome c administration, antigen-specific systemic T cell activation is induced, and spleen cells gain the ability to stimulate cytochrome c–specific T cell responses. Feeding multiple low doses of cytochrome c down-regulates the systemic immune response, which can be correlated with a reduction of antigen-specific T cells and not with immune deviation. These results suggest that systemic distribution of antigen contributes significantly to oral tolerance induction.