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

项目摘要 尽管干细胞微环境或生态位已被广泛研究为调节 干细胞的功能，免疫属性的利基在很大程度上还没有被探索。有趣的是，研究 60多年前进行的研究揭示了生殖系和胚胎干细胞的位置，睾丸 胎盘，干细胞的免疫庇护所，称为免疫特权(IP)部位。在这些组织中， 移植的同种或异种移植物可以在没有免疫抑制治疗的情况下存活，区分IP 来自其他站点的站点。关于组织承诺的干细胞利基是否作为IP位点，人们知之甚少。我们的 最近的研究表明，骨髓(BM)中的HSC生态位是一种IP 地点。我们发现独特的FoxP3+调节性T细胞(Tregs)具有HSC标记的高表达， CD150，常定位于HSC附近。这些树使allo-HSC能够在非 无免疫抑制的条件性免疫能力强小鼠。在非移植环境中，生态位树 保护内源性HSC免受氧化应激，保持HSC静止。这些观察结果表明 这种利基树赋予HSCs免疫特权。促进我们的研究成果转化为临床 背景下，我们将建议研究NICE树在造血失败中的作用和治疗潜力 照射后和非清髓性条件处理后的异基因造血干细胞植入。我们将描述 生态位树的抗逆性、再生潜能、分子特征和T细胞受体(TCR) 曲目，评估这些小生境树的特征如何有助于保护或植入HSC。 成功的研究将识别史无前例的Treg亚群，它们作为干细胞保护剂免受免疫 攻击和应激，破译这种利基Treg介导的干细胞保护或 植入，并导致有希望的治疗策略的发展后，骨髓损伤或 通过转移或操纵壁龛进行嫁接。因此，我们建议的研究结果将 最终改善异基因骨髓移植或血液病患者的放射治疗结果， 免疫缺陷、代谢性疾病、血液恶性肿瘤和实体癌。

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.