Physical contact between thymocytes and the thymic stroma is essential for the establishment of self-tolerance, and Aire in thymic epithelial cells plays an important role in this action. As expected, the autoimmune phenotypes of Aire-deficient mice are thymic stroma-dependent. Interestingly, the spectrum of the organs involved differs depending on the genetic background of non-autoimmune-prone mouse strains. Furthermore, deficiency of Aire in an autoimmune-prone strain of NOD also modifies target-cell specificity in the pancreas. In order to clarify the factors that regulate target-organ specificity in Aire-dependent autoimmunity, I have generated both thymic and bone-marrow chimeras, making it possible to evaluate the contribution of thymic stroma and bone-marrow-derived cells to this pathogenic process. The findings suggested that the genetic background of bone-marrow-derived cells contributes to the strain-dependent target-organ specificity of non-autoimmune-prone strains. Furthermore, in a study using NOD mice with a fixed genetic background, thymic stromal cells but not bone-marrow-derived cells were found to be relevant to the Aire-dependent alteration of target-cell specificity in the pancreas. These results clearly underscore the significance of immunological and/or genetic complexity that underlies Aire-deficiency monogenic disease together with critical dialogue between thymic stroma and bone-marrow-derived cells in the organized thymic microenvironment.