Sublethally irradiated, immunodeficient, C57BL/6 RAG‐2 gene‐deleted recipient mice reconstituted with T cell‐depleted bone marrow (BM) grafts frequently developed diarrhea, lost weight and showed signs of autoimmunity, dying between 4 and 7 weeks after reconstitution. Mice died despite evidence of efficient donor‐derived hemato‐lymphoid reconstitution, and disease was associated with the presence of IgG anti‐nuclear antibodies. Autoimmunity was initiated by T cells, but could be prevented by transfer of naturally arising regulatory T cells. In contrast, lethally irradiated, BM‐reconstituted immunocompetent, C57BL/6 mice survived without signs of autoimmunity. Survival of immunocompetent mice was shown to be due to the presence of residual, extra‐thymically located, radio‐resistant, functional regulatory T cells. The importance of regulatory T cells was further shown by the reduced survival of immunocompetent BM recipients whose CD25⁺ T cells had been depleted prior to bone marrow transplantation. The implications of these results in the context of syngeneic graft‐versus‐host disease following BM transplantation are discussed.

See accompanying commentary: http://dx.doi.org/10.1002/eji.200636571