Abstract Guinea pigs immunized with ABA-tyr in CFA respond well by skin test to ABA-tyr-pulsed macrophages but poorly to ABA-coupled macrophages and not at all to ABA-coupled red cells, thymocytes, or L 2C cells. On the other hand, guinea pigs immunized with ABA-coupled macrophages do not respond to ABA-insulin or ABA-tyr-pulsed macrophages but do respond to ABA-coupled macrophages. Similarly guinea pigs immunized with Ars-NCS-coupled macrophages respond only to the homologous antigen. The specificity of these reactions is determined by how ABA is associated with the Ia-positive accessory cell. The presence of Ia molecule is not a sufficient condition since neither Ia-positive L 2C cells nor spleen cells depleted of adherent macrophages are effective as immunogens or elicitors of response when coupled with ABA. These results suggest that the topography of the ABA and Ia complex formed on the accessory cell is the prime determinant of specificity for T-cells responses.