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

在过去的十年中，在各种实体和血液恶性肿瘤中由适应性免疫系统介导的癌症免疫已经获得了牵引力。增强和激活抗肿瘤免疫的各种方法已经导致癌症治疗的巨大进步。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、损害患者的抗肿瘤应答和限制免疫选择的成功，对实体和血液恶性肿瘤中的肿瘤行为具有重大影响。相反，调节机制对异基因干细胞移植后移植物抗宿主病的发展/治疗具有有益作用。最近的研究表明，T细胞介导的免疫调节主要集中在CD 4 + CD 25 + FoxP 3+调节性T细胞CD 8+调节性T细胞（CD 4 + Treg）的调节活性，而且还显示出对B和自然杀伤细胞以及髓源性抑制细胞亚群的调节活性。然而，迄今为止，在肿瘤免疫和同种异体干细胞移植后的免疫重建期间，CD 8 + Treg的功能仍然难以捉摸。最近在小鼠中鉴定了一种新的CD 8 + Treg亚群，其代表约5%的CD 8 + T细胞，其特征在于表达CD 44 + CD 122 + Ly 49 +Helios+表型。这种T细胞亚群对于维持自身耐受性至关重要，并且在抗病毒免疫和抗肿瘤作用中起主要作用。本研究的目的是：1）验证小鼠CD 8 + Treg在移植物抗宿主病（GvHD）中的抑制机制; 2）确定人CD 8 + Treg在异基因干细胞移植后人GvHD发展中的功能相关性。为了研究体内⑶ 8 + Treg在GvHD中的抑制作用，将使用完善的急性小鼠模型。这些知识将用于评估人CD 8 + Treg，并评估其对异基因干细胞移植后患者的急性和慢性GvHD的影响。这些研究如果成功，将为开发用于预防和/或治疗GvHD患者的新型免疫策略开辟新的途径。

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.