ATROPHIED THYMUS-GENERATED TH17 CELL INVOLVEMENT IN AUTOIMMUNITY IN THE ELDERLY

Purpose: Aging induced thymic involution is proposed to be related to an increased incidence of autoimmune disorders because one of roles of a functional thymus is to generate central immune tolerance to prevent autoimmunity. Th17 cells have been shown to play a role in autoimmunity and can be generated in the thymus. Therefore, it can be questioned whether self-reactive Th17 clones can be generated in the aged atrophied thymus and become involved in the process of autoimmune development in the elderly once being induced under certain circumstances. Methods: We used conditional FoxN1 knockout (FC) mice, which possess an atrophied thymus, mimicing aged mice when injected with tamoxifen. The control mice with the normal thymus are termed FF. We used a cell sorting approach to isolate CD4 single positive thymocytes and naive CD4 positive spleen T cells. Sorted cells were cultured in conditions to induce Th17 differentiation. Flow cytometry was used to analyze cell populations. We used Rag gene knockout mice as hosts to receive Th17 cell infusion for observation of autoimmune phenotypes by histochemistry. Results: 1. The percentage of induced Th17 thymocytes is higher in FC mice compared to FF mice, but without induction there is no difference in FC and FF two groups. This indicates that when given a stimulus such as infection the atrophied thymus may produce a higher percentage of auto-reactive Th17 cells compared to a normal thymus. 2. The percentage of induced Th17 splenocytes and non-induced Th17 splenocytes shows no difference between FC and FF mice. However, there is greater inflammation and cell infiltration in the organs (such as the colon and lung) in the Rag-/- mice infused with FC Th17 compared to that infused with FF Th17. The result shows that although the percentage of Th17 cells from an atrophied thymus is not affected in the periphery, they may have higher auto-reactive activity compared to a normal thymus. Conclusions: The atrophied thymus may be defective in the generation of central immune tolerance and therefore allow auto-reactive Th17 cells to survive and leave the thymus.