Defining the role of CD8+ regulatory T cells in Graft-versus-Host Disease after allogeneic stem cell transplantation.

在过去的十年里，由适应性免疫系统在各种实体和血液系统恶性肿瘤中介导的癌症免疫已经获得了吸引力。增强和激活抗肿瘤免疫的各种方法使癌症治疗取得了巨大的进步。然而，肿瘤微环境中的体液和细胞免疫抑制通过允许肿瘤逃逸、损害患者的抗肿瘤反应和限制免疫治疗方案的成功而对实体和血液系统恶性肿瘤的肿瘤行为产生重大影响。相反，调节机制在异基因干细胞移植后移植物抗宿主病的发展/治疗中具有有利的作用。最近的研究表明，T细胞介导的免疫调节主要集中在CD4+CD25+FoxP3+调节性T细胞(CD4+Treg)，但也显示出B亚群和自然杀伤细胞以及髓系抑制细胞的调节活性。然而，CD8+调节性T细胞(CD8+Treg)在肿瘤免疫和异基因干细胞移植后免疫重建中的作用机制至今仍不清楚。最近在小鼠中发现了一种新的CD8+Treg亚群，占CD8+T细胞的5%，其特征是表达CD44+CD122+Ly49+Helios+表型。T细胞亚群是维持自身耐受性的关键，在抗病毒免疫和抗肿瘤作用中发挥重要作用。此外，初步结果提示异基因干细胞移植后CD8+Treg的调节活性。本方案的目的是：1)验证小鼠CD8+Treg在移植物抗宿主病(GvHD)中的抑制机制；2)确定人CD8+Treg与异基因干细胞移植后人类GvHD发生发展的功能相关性。为了在体内研究CD8+Treg对移植物抗宿主病的抑制作用，我们将使用一个公认的急性小鼠模型。这些知识将被用来评估人类CD8+Treg，并评估它们对异基因干细胞移植后患者急性和慢性GvHD的影响。如果这些研究成功，将为开发预防和/或治疗GvHD患者的新的免疫治疗策略开辟一条新的途径。

Cancer immunity mediated by the adaptive immune system in various solid and hematological malignancies has gained traction in the last decade. Various approaches to enhance and activate anti-tumor immunity have led to tremendous advances in cancer treatment. Humoral and cellular immunosuppression in the tumor-microenvironment, however, have a major impact on tumor behavior in solid and hematologic malignancies by allowing tumor escape, impairing the anti-tumor response in patients and constricting the success of immunotherapeutic options. In contrast, regulatory mechanisms have beneficial effects on the development/treatment of Graft-versus-Host Disease after allogeneic stem-cell transplantation. Recent studies have demonstrated the contribution of T cell-mediated immune regulation mainly focusing on CD4+CD25+FoxP3+ regulatory T cells (CD4+ Treg), but also showing regulatory activity of subsets of B and natural killer cells as well as myeloid derived suppressor cells.The mechanisms of CD8+ regulatory T cell (CD8+ Treg) function in tumor immunity and during immune reconstitution after allogeneic stem cell transplantation, however, remain elusive until now. Recently a novel CD8+ Treg subset has been identified in mice, which represents ~5% of CD8+ T cells and is characterized by expression of the CD44+CD122+Ly49+Helios+ phenotype. This T cell subset is critical to maintain self-tolerance and plays major roles in anti-viral immunity and anti-tumor effects. Additionally, preliminary results suggest regulatory activity of CD8+ Treg after allogeneic stem cell transplantation.The objectives of this proposal are 1) to validate the suppressive mechanisms of murine CD8+ Treg in Graft-versus-Host Disease (GvHD) and 2) to determine the functional relevance of human CD8+ Treg for the development of human GvHD after allogeneic stem cell transplantation. To interrogate the inhibitory effects of CD8+ Treg in GvHD in vivo a well-established acute mouse model will be used. This knowledge will be used to assess human CD8+ Treg and evaluate their impact on acute and chronic GvHD in patients after allogeneic stem-cell transplantation. These studies, if successful, will open a new avenue for the development of novel immunotherapeutic strategies for the prevention and/or treatment of patients with GvHD.