The thymus, which is the primary site of T cell development, is extremely sensitive to insult but also has a remarkable capacity for endogenous repair. However, even though there is continual thymic involution and regeneration in response to everyday insults like stress and infection, profound thymic damage, such as ionizing radiation, leads to prolonged T cell lymphopenia. One approach to developing therapies to boost thymic function after radiation injury is to understand and exploit the processes underlying endogenous repair.
We have identified that the balance of cell death detection is crucial for triggering endogenous regenerative responses in the thymus. Specifically, immunologically silent apoptosis (which is abundant in thymocytes during steady-state) is suppressive to the regenerative program, but in contrast, after thymic damage, a switch toward immunogenic cell death (ICD) can promote regeneration. Importantly, many of these pathways can be therapeutically targeted to improve thymic recovery after radiation injury. However, induction of ICD (and specifically the cleavage of caspase-1) also leads to the activation of proinflammatory factors such as IL-18 and IL-1β. Although IL-1β did not seem to impact regeneration after injury, IL-18 limited repair by stimulating NK cells and their cytotoxic program, which targets thymic epithelial cells, which are crucial for supporting T cell development. Notably, this proinflammatory axis is not the only limitation to thymus repair, with aging-associated epithelial remodeling also contributing to blunted regenerative responses with age.
Together, these studies not only further defined the cellular and molecular regulators of thymic damage and repair after injury but also demonstrated the critical need for balancing proregenerative and suppressive signals in developing optimal therapies for thymus recovery and T cell reconstitution.
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号