Athymic nude mice implanted with F1 thymus glands were used to investigate genetic restrictions regulating T cell-macrophage (MΦ) interactions in the development of antibody responses to GAT. Spleen cells from conventional mice developed comparable primary plaque-forming cell (PFC) responses when stimulated by syngeneic and allogeneic GAT-MΦ. However, spleen cells from strain A nude mice implanted with (A x B)F1 thymus glands were tolerant of strain B alloantigens and developed GAT-specific PFC responses to strain A GAT-MΦ and allogeneic strain C GAT-MΦ, but failed to respond to strain B GAT-MΦ. The lack of primary GAT-specific PFC responses by spleen cells from (A x B)thy → A nude mice stimulated by strain B GAT-MΦ was not due to detectable suppressor mechanisms. However, an allogeneic effect stimulated by H-2- or non-H-2-disparate GAT-pulsed or unpulsed MΦ was able to overcome the inability of spleen cells from (A x B)F1 thy → A nude mice to respond to strain B GAT-MΦ. Furthermore, the inability to respond to strain B GAT-MΦ was overcome by the addition of supernatant fluids from independent cultures of H-2-disparate cells. These results 1) demonstrate that T cells from A nude mice implanted with (A x B)F1 thymus glands did not recognize nominal antigen in the context of B MHC antigens, and 2) suggested that the T cell repertoire was altered in strain A nude mice implanted with (A x B)F1 thymus glands, such that T cells that could recognize GAT in association with strain B MHC antigens were functionally deleted.