B6.g7 mice reconstituted with BDC2·5 non‐obese diabetic (BDC2·5NOD) stem cells do not develop autoimmune diabetes

Summary In BDC2·5 non‐obese diabetic (BDC2·5NOD) mice, a spontaneous model of type 1 diabetes, CD 4 + T cells express a transgene‐encoded T cell receptor ( TCR ) with reactivity against a pancreatic antigen, chromogranin. This leads to massive infiltration and destruction of the pancreatic islets and subsequent diabetes. When we reconstituted lethally irradiated, lymphocyte‐deficient B 6.g7 ( I ‐ A g7+ ) R ag –/– mice with BDC2·5NOD haematopoietic stem and progenitor cells (HSPC; ckit + Lin – Sca‐1 hi ), the recipients exhibited hyperglycaemia and succumbed to diabetes. Surprisingly, lymphocyte‐sufficient B 6.g7 mice reconstituted with BDC 2·5 NOD HSPC s were protected from diabetes. In this study, we investigated the factors responsible for attenuation of diabetes in the B 6.g7 recipients. Analysis of chimerism in the B 6.g7 recipients showed that, although B cells and myeloid cells were 98% donor‐derived, the CD 4 + T cell compartment contained ∼50% host‐derived cells. These host‐derived CD 4 + T cells were enriched for conventional regulatory T cells ( T regs ) ( CD 25 + forkhead box protein 3 ( F oxP3) + ] and also for host‐ derived CD4 + CD25 – FoxP3 – T cells that express markers of suppressive function, CD 73, FR 4 and CD 39. Although negative selection did not eliminate donor‐derived CD 4 + T cells in the B 6.g7 recipients, these cells were functionally suppressed. Thus, host‐derived CD 4 + T cells that emerge in mice following myeloablation exhibit a regulatory phenoytpe and probably attenuate autoimmune diabetes. These cells may provide new therapeutic strategies to suppress autoimmunity.