Jagged1 overexpression on T cells induces thymic regulatory T cells leading to thymic involution

Abstract

We previously described a mouse model, tg66, with a severe defect resulting in diminished thymic size and complete involution by early adulthood. In the current study, we identified overexpression of Jagged1 as a mechanism for the alterations in thymic development in tg66 mice. T cells in the tg66 thymus were skewed towards CD8+ T cells, and within the CD4+ T cell compartment there was an over-representation of Foxp3+ cells. Regulatory Foxp3+ T cells (Tregs) isolated from tg66 mice had increased ST2 and CD103 expression. These Tregs could suppress proliferation to the same extent as conventional Tregs. Corroborating these results, tg66 mice were resistant to experimental induction of neuroinflammation in a common animal model for multiple sclerosis (EAE). Using bone marrow chimeras, we recorded a stark reduction in the number of thymocytes and a corresponding increase in Tregs in the thymus of mice receiving tg66 bone marrow. Conversely, through blocking Jagged1, the number of thymocytes was significantly increased, being concomitantly associated with a drop in the frequency of Tregs. We conclude that Tregs may play a role in thymic involution and could explain early thymic involution or loss as it is observed in diseases of thymic atrophy such as Down syndrome.