Department of Immunology, University of Toronto, Toronto, ON, Canada.
Sunnybrook Research Institute, Toronto, ON, Canada.
Front Immunol. 2020 Aug 18;11:1850. doi: 10.3389/fimmu.2020.01850. eCollection 2020.
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 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 -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 细胞在介导针对病毒和细菌病原体的抗原特异性和长期免疫方面发挥着关键作用,其发育依赖于高度特化的胸腺微环境。T 细胞免疫缺陷既可以是先天的,也可以是由于衰老或癌症治疗所需的辐射/化疗对胸腺的干扰所致。来自相容供体的造血干细胞移植(HSCT)是治疗血液系统恶性肿瘤和免疫缺陷的基石。尽管它可以重建功能性免疫系统,但 T 细胞区室的恢复仍存在严重障碍。HSCT 后,T 细胞在许多个月内仍然缺失或数量较少,具体取决于多种因素,包括受者的年龄。虽然年轻患者的无反应期较短,但老年患者观察到的 T 细胞恢复时间延长会导致机会性感染风险增加和复发倾向增加。因此,需要制定增强老年个体 T 细胞恢复的策略,以对抗辐射和化疗毒性引起的胸腺损伤,以及自然发生的与年龄相关的胸腺萎缩。临床前结果表明,当在 HSCT 期间共给予来自 HSCs 的祖 T 细胞时,可以实现强大且快速的长期胸腺重建。祖 T 细胞似乎依赖于通过 NF-κB(RANK)和 RANKL(RANKL)受体激活剂的淋巴基质串扰,在皮质和髓质内创建富含趋化因子的小生境,这可能有利于招募骨髓衍生的胸腺播种祖细胞。在这里,我们使用临床前小鼠模型证明了生成的祖 T 细胞可以有效地植入退化的老年胸腺,这可能有助于改善 T 细胞恢复。祖 T 细胞在老年受者中的应用将其定位为一种有前途的细胞疗法,用于在辐射和化疗后进行免疫恢复和胸腺内修复,即使在退化的胸腺中也是如此。