Thymic involution is the process of atrophy observed to take place in the thymus with age. The thymus is a small, but critical organ. Thymocytes produced in the bone marrow migrate to the thymus where they mature into T cells of the adaptive immune system. As active thymic tissue is replaced with fat, the supply of T cells falls to a fraction of youthful levels. This loss of replacement cells is an important contributing factor in the age-related decline of the adaptive immune system. T cell populations come under increasing replicative stress as they strive to maintain a consistent number of circulating cells, while pathological subpopulations of broken and malfunctioning T cells accumulate.
Why does the thymus atrophy? Researchers have studied the signaling involved, and it is reasonable to put much of the blame on rising levels of chronic inflammation with age. That is likely not the whole story, however, as chronic inflammation is a very broad set of mechanisms and interactions, as well as being associated with many other forms of immune dysfunction. We should expect to see discoveries such as that reported in today's open access paper, in which the authors delve into a very specific aspect of immune function that can both correlate with chronic inflammation, and gradually deplete thymic tissue over a lifetime.
The thymus is the central immune organ of the body and critical for T-cell differentiation and development. Many different cell types including thymocytes and thymic stromal cells such as thymic epithelial cells (TECs), resident macrophages, and dendritic cells (DCs) are present in the thymus. As the most crucial stromal cells in the thymus, TECs consist of the cortex and medulla TECs and control the positive and negative selection of T cells. The volumes of the thymic epithelium (cortex and medulla) show a continuous involution from the first year to the end of life. During thymus degeneration, TECs are replaced by fibrocytes and adipocytes. Decreased thymopoiesis leads to a decreased output of naïve T cells with reduced TCR repertoire and diversity. In addition, the number of naïve T cells in peripheral blood decreases gradually.
The increasing evidence demonstrated that peripheral DCs can migrate into the thymus. It was reported that two of the three major subsets of thymic DCs originate extrathymically and continually migrate to the thymus. It has been demonstrated that bone marrow derived antigen-presenting cells (APCs) carrying antigens from the periphery migrate into the thymus and delete autoreactive cells. Futher studies noted that circulating DCs migrated into the thymus and interacted with thymocytes.
In this study, mature DCs (mDCs), generated from the GM-CSF and IL-4 induced bone marrow cells, were intravenously injected into wild-type mice. Three days later, assays showed that the mDCs were indeed able to return to the thymus. Homing DCs have been mainly reported to deplete thymocytes and induce tolerance. However, medullary TECs (mTECs) play a crucial role in inducing immune tolerance. Thus, we evaluated whether the mDCs homing into the thymus led to TECs depletion. We cocultured mDCs with mTEC1 cells and found that the mDCs induced the apoptosis and inhibited the proliferation of mTEC1 cells. These effects were only achieved via direct cell-cell contact between mDCs and mTEC1 cells. Furthermore, we observed that an intrathymic injection of the mDCs resulted in acute thymic atrophy and reduced thymocytes and TECs substantially in vivo. In sum, this demonstrated that circulating mDCs migrated into the thymus and induced the degeneration of the thymus.
Overall, the findings of this study improve our understanding of the mechanisms underlying thymus degeneration. During infection, activated DCs are mature, and migrate into different lymph nodes through afferent lymphatic vessels. DCs, residing in tissues, can reach the periphery and carry antigens to secondary lymphoid organs through blood. A small number of circulating DCs, capturing pathogens, can migrate into thymus. Although the number of thymic homing DCs is relatively small, given numerous mild or severe infections throughout our lifetime, the cumulative effects may contribute to age-related thymus degeneration.
In summary, our results provided evidence that circulating mDCs return to the thymus and interact directly with TECs to activate Notch signaling through the Jagged1/Notch3 axis. Long-term Notch signaling activation of TECs results in their apoptosis and growth inhibition, thus leading to the degeneration of the thymus. These results also provide insights into the mechanisms underlying age-related thymic atrophy or infection, organ transplant rejection, and other diseases related acute thymic atrophy and help to develop novel strategies in clinical thymus and T-cell reconstruction.