Tissue-specific autoimmunity manipulated by Aire in thymic and peripheral tolerance

Tissue-specific autoimmune diseases are assumed to arise from the malfunction of two checkpoints for immune tolerance: defect in the elimination of autoreactive T-cells in the thymus, and activation of these T-cells by the corresponding autoantigens in periphery. However, evidence for this model and outcome of the alterations in individual or both tolerance mechanisms have not been sufficiently studied.Here, we have investigated these issuesby introducing human AIRE (huAIRE)as a modifier for tolerance mechanism in NOD in which the defect in the thymic and peripheral tolerance coordinately causes type I diabetes. Transgenic expression of huAIRE in thymic stroma did not affect the production of diabetogenic T-cells in the thymus. In contrast, transgenic huAIRE expression in peripheral antigen-presenting cells (APCs) resulted in the resistance to the diabetes due to their inability to activate diabetogenic T-cells producedin the thymus. These results were contrasting to our recent demonstration that huAIRE expression both in thymic stromaland peripheral APCs resulted in the development of muscle-specific autoimmunity. Our results highlighted that tissue-specific immune response is positively or negatively controlled by the coordinated action between thymic and peripheral tolerance mechanism, which can be manipulated by the expression of huAIRE/Aire in each component or both.