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Understanding the difference between the development of a productive T‐cell response and tolerance is central to discerning how the immune system functions. Intravenous injection of soluble protein is thought to mimic the presentation of self‐serum and orally introduced antigens. It is generally toleragenic. The current view is that this outcome reflects the failure of ‘immunogenic’ dendritic cells to relocate to the T‐cell zone of the secondary lymphoid tissues. Here, using a peptide/I‐E^k tetramer and antibodies to stain splenic sections, we showed that antigen‐specific T cells were activated in the spleen within hours of injection or feeding of protein. The activated T cells were found to be located at the T–B junction, the bridging zone and the B‐cell area, interacting directly with B cells. In addition, B cells gain the ability to present antigen. Our results suggest a way for T cells to be stimulated by blood‐borne antigen …