Summary The ability of thymic epithelial cells (TEC) to re‐educate mature T cells to be regulatory T cells has not been addressed. In the present study, this issue was directly investigated by co‐culturing of mature T cells and allo‐TECs. B6 macrophage cell line 1C21‐cultured BALB/c splenocytes responded to B6 antigens in vitro. However, BALB/c splenocytes precultured with B6‐derived TECs 1‐4C18 or 1C6 did not proliferate to B6 antigens, but responded to rat antigens. Exogenous interleukin‐2 (IL‐2) failed to revise the unresponsiveness of these T cells. Allo‐TEC‐cultured T cells predominantly expressed Th2 cytokines (IL‐4 and IL‐10). B6 TEC‐cultured BALB/c splenocytes markedly inhibited the immune responses of naïve BALB/c splenocytes to B6 antigens, but not to rat or the third‐party mouse antigens. BALB/c nude mice that received naïve syngeneic splenocytes rejected B6 or rat skin grafts by 17 days postskin grafting; however, co‐injection of B6 TEC‐cultured BALB/c splenocytes significantly delayed B6 skin graft rejection (P < 0.01), with the unchanged rejection of rat skin grafts. These studies demonstrate that allo‐TECs are able to ‘educate’ mature T cells to be regulatory cells, and suggest that regulatory cells derived from mature T cells by TECs may play an important role in T cell tolerance to allo‐ and auto‐antigens.

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