Data_Sheet_1_Thymic Engraftment by in vitro-Derived Progenitor T Cells in Young and Aged Mice.docx

T cells play a critical role in mediating antigen-specific and long-term immunity against viral and bacterial pathogens, and their development relies on the highly specialized thymic microenvironment. T cell immunodeficiency can be acquired in the form of inborn errors, or can result from perturbations to the thymus due to aging or irradiation/chemotherapy required for cancer treatment. Hematopoietic stem cell transplant (HSCT) from compatible donors is a cornerstone for the treatment of hematological malignancies and immunodeficiency. Although it can restore a functional immune system, profound impairments exist in recovery of the T cell compartment. T cells remain absent or low in number for many months after HSCT, depending on a variety of factors including the age of the recipient. While younger patients have a shorter refractory period, the prolonged T cell recovery observed in older patients can lead to a higher risk of opportunistic infections and increased predisposition to relapse. Thus, strategies for enhancing T cell recovery in aged individuals are needed to counter thymic damage induced by radiation and chemotherapy toxicities, in addition to naturally occurring age-related thymic involution. Preclinical results have shown that robust and rapid long-term thymic reconstitution can be achieved when progenitor T cells, generated in vitro from HSCs, are co-administered during HSCT. Progenitor T cells appear to rely on lymphostromal crosstalk via receptor activator of NF-κB (RANK) and RANK-ligand (RANKL) interactions, creating chemokine-rich niches within the cortex and medulla that likely favor the recruitment of bone marrow-derived thymus seeding progenitors. Here, we employed preclinical mouse models to demonstrate that in vitro-generated progenitor T cells can effectively engraft involuted aged thymuses, which could potentially improve T cell recovery. The utility of progenitor T cells for aged recipients positions them as a promising cellular therapy for immune recovery and intrathymic repair following irradiation and chemotherapy, even in a post-involution thymus.

T细胞在调节针对病毒和细菌病原体的抗原特异性及长期免疫过程中扮演着至关重要的角色，其发育依赖于高度专业化的胸腺微环境。T细胞免疫功能缺陷可由先天性疾病引起，或因年龄增长、放疗/化疗等癌症治疗手段导致的胸腺损伤所导致。来自兼容供体的造血干细胞移植（HSCT）是治疗血液恶性肿瘤和免疫缺陷的基础治疗方法。尽管它能够恢复功能性的免疫系统，但T细胞库的恢复却存在深刻的障碍。在HSCT后，T细胞数量可能长时间保持缺失或低水平，这取决于接受者年龄等多种因素。虽然年轻患者的恢复期较短，但老年患者观察到的T细胞恢复期延长可能导致机会性感染风险增加和复发倾向加剧。因此，针对老年个体增强T细胞恢复的策略是必要的，这不仅为了对抗放疗和化疗毒性的胸腺损伤，还为了对抗自然发生的与年龄相关的胸腺退化。临床前研究结果已表明，当源自HSCs的祖性T细胞在HSCT期间共同给药时，可以实现快速且持久的长期胸腺重建。祖性T细胞似乎依赖于通过RANK（核因子κB受体活化因子）和RANKL（RANK配体）相互作用的淋巴基质间的信号交流，在皮质和髓质内形成富含趋化因子的微环境，这可能会促进骨髓来源的胸腺种子祖细胞的募集。在本研究中，我们采用了临床前小鼠模型，证明了体外生成的祖性T细胞可以有效地植入退化的老年胸腺，这有可能改善T细胞的恢复。对于老年受者而言，祖性T细胞在免疫恢复和胸腺内修复方面的应用，将其定位为一种很有前景的细胞治疗手段，即使在胸腺退化的情况下，也能在放疗和化疗后发挥效用。