Abstract
Multiple proinflammatory conditions, including chemotherapy, radiotherapy, transplant rejection, and microbial infections, have been identified to induce involution of the thymus. However, the underlying cellular and molecular mechanisms of these inflammatory conditions inducing apoptosis of thymic epithelial cells (TECs), the main components of the thymus, remain largely unknown. In the circulation, mature dendritic cells (mDCs), the predominant initiator of innate and adaptive immune response, can migrate into the thymus. Herein, we demonstrated that mDCs were able to directly inhibit TECs proliferation and induce their apoptosis by activating the Jagged1/Notch3 signaling pathway. Intrathymic injection of either mDCs or recombinant mouse Jagged1-human Fc fusion protein (rmJagged1-hFc) into mice resulted in acute atrophy of the thymus. Furthermore, DAPT, a γ-secretase inhibitor, reversed the effects induced by mDC or rmJagged1-hFc. These findings suggest that acute or aging-related thymus degeneration can be induced either by mass migration of circulating mDCs in a short period of time or by a few but constantly homing mDCs.
Highlights
The thymus, as a central immune organ, is mainly responsible for T lymphocytes production
Almost all GFP+ cells were CD11c positive repression of Notch signaling is critical for medullary thymic (Fig. 1D). These results indicated that circulating mature dendritic cells (mDCs) were able to epithelial cells development [19]
In this study, we examined whether circulating Dendritic cells (DCs) migrated into the thymus and induced Jagged1 was highly expressed in mDCs, while Notch3 was the degeneration of thymic epithelial cells (TECs) via Notch signaling
Summary
The thymus, as a central immune organ, is mainly responsible for T lymphocytes production. Almost all GFP+ cells were CD11c positive repression of Notch signaling is critical for medullary thymic (Fig. 1D) These results indicated that circulating mDCs were able to epithelial cells (mTECs) development [19]. Expression of Notch reduced the populations of total TECs and mTECs, suggesting that Notch signaling promotes the degenera- Mature DCs promoted cell apoptosis and inhibited TECs tion of the mTEC lineage [19] Taken together, these findings proliferation through cell–cell contact indicate that Notch signaling plays complex roles in thymic To examine the effects of homing DCs on TECs, we cocultured the development and degeneration. In this study, we examined whether circulating DCs migrated into the thymus and induced Jagged was highly expressed in mDCs, while Notch was the degeneration of TECs via Notch signaling
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