How the mucosal immune system promotes active immunity against harmful organisms but tolerance to commensal bacteria or dietary antigens is poorly understood. Thus, the antigen-presenting cell (APC), site of antigen presentation, and effector mechanisms responsible for oral priming and tolerance remain unclear. Characterizing differences between oral priming and tolerance may improve the exploitation of oral tolerance for therapeutic applications and aid the design of oral vaccines. To address these questions we compared the mucosal and systemic activation and localization of antigen-specific T cells during the induction of oral priming and tolerance. Activation marker expression and cell division by tg T cells was determined in conjunction with their anatomical location. These studies show that after feeding, T cells are activated in both peripheral and local lymphoid tissues within 6 hr, irrespective of the presence of adjuvant. Subsequently, T-cell accumulation can be detected simultaneously in peripheral and mesenteric lymph nodes and Peyer's patches within 24 hr of feeding, but only after 3 days post feeding in the lamina propria. Primed and tolerized T cells adopted similar phenotypes as assessed by activation marker expression. However, within the mesenteric lymph nodes (MLN) tolerized T cells underwent significantly fewer divisions than primed T cells. Thus, T-cell activation and expansion occurs throughout the animal after feeding a range of doses of antigen, irrespective of whether priming or tolerance is the eventual outcome. However, the presence of an adjuvant enhances clonal expansion in the MLN while tolerized T cells display defective cell division.