Dudakov Jarrod A, van den Brink Marcel R M
Translational Science and Therapeutics Division, and Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Department of Immunology, University of Washington, Seattle, Washington, USA.
Immunol Rev. 2025 Jul;332(1):e70050. doi: 10.1111/imr.70050.
The thymus 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 for which there is currently no therapeutic treatment. We and others have been focusing in recent years on untangling the cellular and molecular mechanisms underlying endogenous thymic regeneration in the hope of being able to exploit them for clinical benefit. To date, multiple molecular mechanisms have been identified that are centered on several distinct cell axes, including interleukin-22 produced by innate lymphoid cells, BMP4 by endothelial cells, and type 2 cytokines from eosinophils, ILCs, and Tregs. Notably, one of the uniting triggers for these pathways of repair centers on the balance of cell death detection. In this review, we will highlight the current state of play with regard to cellular and molecular pathways of regeneration as well as the mechanisms triggering them. We will also highlight recent work that sheds light on the limitations of thymus repair and speculate as to what will be needed for an effective thymus-boosting therapy.
胸腺对损伤极其敏感，但同时也具有显著的内源性修复能力。然而，尽管胸腺会因日常应激和感染等损伤而持续发生退化和再生，但诸如电离辐射等严重的胸腺损伤会导致长期的T细胞淋巴细胞减少症，目前尚无针对该病症的治疗方法。近年来，我们和其他研究人员一直致力于梳理胸腺内源性再生的细胞和分子机制，以期能够将其用于临床治疗。迄今为止，已经确定了多种分子机制，这些机制集中在几个不同的细胞轴上，包括固有淋巴细胞产生的白细胞介素-22、内皮细胞产生的骨形态发生蛋白4，以及嗜酸性粒细胞、固有淋巴细胞和调节性T细胞产生的2型细胞因子。值得注意的是，这些修复途径的一个共同触发因素集中在细胞死亡检测的平衡上。在这篇综述中，我们将重点介绍再生的细胞和分子途径以及触发这些途径的机制的当前研究状况。我们还将重点介绍揭示胸腺修复局限性的近期研究，并推测有效的胸腺增强疗法需要具备哪些条件。
