Roles and therapeutic potential of CD150high niche-associated regulatory T cells in bone marrow injury and engraftment

CD150高生态位相关调节性T细胞在骨髓损伤和植入中的作用和治疗潜力

• 批准号: 10322010
• 负责人: Joji Fujisaki
• 金额: $ 28.51万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322010
• 关键词: Roles; therapeutic; potential; CD150high; niche

Project Abstract Although the stem cell microenvironment, or the niche, has been extensively studied as a site which regulates stem cell functions, immunological attributes of the niche have been largely unexplored. Interestingly, studies conducted over six decades ago revealed that the locations of germline and embryonic stem cells, the testis and placenta, immunological sanctuaries for stem cells, termed immune privileged (IP) sites. In these tissues, transplanted allogeneic or xenogeneic grafts can persist without immune suppressive therapy, distinguishing IP sites from other sites. Little is known about whether tissue-committed stem cell niches serve as IP sites. Our recent studies demonstrated evidence suggesting that the HSC niche within the bone marrow (BM) is an IP site. We showed that unique FoxP3+ regulatory T cells (Tregs) with high expression of an HSC marker, CD150, frequently localized adjacent to HSCs. These Tregs enabled persistence of allo-HSCs in non- conditioned immune competent mice without immune suppression. In non-transplantation settings, niche Tregs protected endogenous HSCs from oxidative stress, maintaining HSC quiescence. These observations suggest that niche Tregs endow HSCs with immune privilege. To promote translation of our findings into clinical settings, we will propose to study roles and therapeutic potential of niche Tregs in hematopoiesis failure following irradiation and in allo-HSC engraftment following non-myeloablative conditioning. We will characterize niche Tregs' stress-resistance, repopulating potential, molecular signatures, and T cell receptor (TCR) repertoire, assessing how these features of niche Tregs contribute to HSC protection or engraftment. Successful studies will identify unprecedented Treg subsets which act as stem cell protectants from immune attack and stress within the niche, decipher mechanisms of this niche Treg-mediated stem cell protection or engraftment, and lead to development of promising therapeutic strategies for post-irradiation BM injury or engraftment by transferring or manipulating niche Tregs. Therefore, the results of our proposed studies will eventually improve outcomes of allo-BM transplantation or radiation therapy for patients with blood disorders, immune deficiency, metabolic diseases, blood malignancies, and solid cancers.

项目摘要 尽管干细胞微环境或生态位作为调节细胞的位点已被广泛研究。 干细胞的功能、生态位的免疫学属性在很大程度上尚未被探索。有趣的是，研究 六十多年前进行的研究揭示了生殖系和胚胎干细胞的位置，即睾丸 胎盘是干细胞的免疫避难所，称为免疫特权（IP）位点。在这些组织中， 移植的同种异体或异种移植物无需免疫抑制治疗即可持续存在，这与 IP 不同 来自其他网站的网站。关于组织定型干细胞生态位是否可作为 IP 位点，人们知之甚少。我们的 最近的研究表明，有证据表明骨髓 (BM) 内的 HSC 生态位是一个 IP 地点。我们展示了具有高表达 HSC 标记的独特 FoxP3+ 调节性 T 细胞 (Treg)， CD150，通常位于 HSC 附近。这些 Tregs 使异基因 HSC 在非 条件免疫小鼠没有免疫抑制。在非移植环境中，利基 Tregs 保护内源性 HSC 免受氧化应激，维持 HSC 静止。这些观察表明 利基 Tregs 赋予 HSC 免疫特权。促进我们的发现转化为临床 在这种情况下，我们将建议研究利基 Tregs 在造血衰竭中的作用和治疗潜力 照射后和非清髓性调理后的同种异体 HSC 植入中。我们将表征 生态位 Tregs 的应激抗性、增殖潜力、分子特征和 T 细胞受体 (TCR) 库，评估利基 Tregs 的这些特征如何有助于 HSC 保护或植入。 成功的研究将鉴定出前所未有的 Treg 亚群，它们可充当干细胞免受免疫的保护剂 利基内的攻击和压力，破译该利基 Treg 介导的干细胞保护机制或 移植，并导致开发出有前景的治疗策略，用于治疗辐射后骨髓损伤或 通过转移或操纵生态位 Tregs 进行植入。因此，我们提出的研究结果将 最终改善血液疾病患者的同种异体骨髓移植或放射治疗的结果， 免疫缺陷、代谢性疾病、血液恶性肿瘤和实体癌。