To investigate the ability of lymph-borne (veiled) dendritic cells (LDC) to acquire and present antigens in vivo, mesenteric lymphadenectomized rats were injected intra-intestinally with antigen and LDC were then purified from thoracic duct lymph. When used as antigen presenting cells with primed spleen cells as responders, the LDC could stimulate antigen-specific proliferation of the responder cells in the absence of exogenous added antigen. As little as 10 mg of ovalbumin (OVA) or horseradish peroxidase (HRP) injected into the ileum and jejunum could sensitize LDC for presentation. LDC acquired antigen within 8 hr of its injection but cells collected more than 24 hr after injection were unable to stimulate a response. Non-dendritic cells (NDC) in the thoracic duct lymph, such as B cells, were unable to present antigen either following intraintestinal injection or after in vitro pulsing. The antigen-specific response was blocked by antibodies to CD4 and major histocompatibility complex (MHC) class II and was totally dependent on the presence of CD4+ cells in the responding population. These studies show that dendritic cells can acquire antigens in vivo and provide a novel approach to the study of intestinal immune responses and oral tolerance.