CD27/CD70 mediated negative regulation of inflammatory T cell responses

异基因造血细胞移植(allo-hct)是一种治疗多种恶性血液病的潜在疗法。 血液学和免疫学疾病。然而，移植物抗宿主病(GVHD)仍然是主要的 并发症，导致显著的发病率和死亡率，尽管目前使用的是免疫抑制剂 治疗。已知GVHD是由供体来源的T细胞识别表达的同种异体抗原引起的 在宿主细胞上，并随后损害宿主正常组织。除了MHC刺激的TCR信号外- 抗原复合体、共刺激通路参与T细胞的激活和功能。共同刺激性 CD27分子是表达在T细胞上的肿瘤坏死因子受体家族成员，其配体CD70是已知的 表达于活化的抗原提呈细胞(APC)和T细胞。以前的研究主要使用病毒 感染模型在很大程度上将这种途径描述为“刺激性的”，是最佳T细胞所必需的 虽然它在allo-HCT中的作用以前尚不清楚。在这个项目中，我们使用了已建立的小鼠 研究CD27/CD70在移植物抗宿主病中作用的模型。我们的结果揭示了一种新的抑制作用 途径如下：1)allo-HCT显示CD27-/-和CD70-/-供者T细胞引起更多 供者T细胞CD27/CD70信号转导抑制同种异体移植 2)作为allo-HCT宿主时，CD27-/-和CD70-/-小鼠均表现出更严重的T细胞反应 GVHD与WT宿主的比较，表明宿主中的CD27/CD70信号抑制同种异体T细胞 回应。初步的机制分析表明，该途径通过限制供体T细胞来抑制GVHD 以供体调节性T细胞非依赖的方式扩增和减少促炎细胞因子。基于 这些结果，我们的中心假设是CD27/CD70信号在抑制移植物抗宿主病中起着新的作用 抑制同种异体炎症T细胞反应。我们提出了三个目标来系统地追踪捐赠者T 该通路的细胞衍生机制、宿主衍生机制和临床相关性 GVHD。了解这些机制对于开发能够控制 GVHD和改善allo-HCT患者的生活质量。

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for a variety of hematologic and immunologic diseases. However, graft-versus-host disease (GVHD) remains the major complication that causes significant morbidity and mortality despite the currently practiced immunosuppressive therapies. GVHD is known to be caused by donor-derived T cells that recognize allogeneic antigens expressed on host cells and subsequently damage host normal tissues. In addition to TCR signaling stimulated by MHC- antigen complex, co-stimulatory pathways are involved in T cell activation and function. The co-stimulatory molecule CD27 is a TNF receptor family member expressed on T cells and its ligand, CD70, is known to be expressed on activated antigen-presenting cells (APC) as well as T cells. Previous studies using mainly viral infection models have largely described this pathway as “stimulatory” and required for optimal T cell responses, while its role in allo-HCT is previously unknown. In this project, we have used established murine models to study the roles of CD27/CD70 in GVHD. Our results reveal a novel inhibitory role played by this pathway as specified in 2 aspects: 1) allo-HCT shows that both CD27-/- and CD70-/- donor T cells caused more severe GVHD than WT donor T cells, suggesting that CD27/CD70 signaling in donor T cells inhibits allogeneic T cell response; 2) when used as hosts for allo-HCT, both CD27-/- and CD70-/- mice exhibited more severe GVHD compared to WT hosts, suggesting that CD27/CD70 signaling in the host inhibits allogeneic T cell response. Initial mechanistic analyses suggest that this pathway inhibits GVHD by limiting donor T cell expansion and reducing pro-inflammatory cytokines in a donor regulatory T cell-independent fashion. Based on these results, our central hypothesis is that CD27/CD70 signaling plays a novel role suppressing GVHD by inhibiting allogeneic inflammatory T cell response. We propose three aims to systematically pursue donor T cell-derived mechanisms, host-derived mechanisms and clinical relevance of this pathway in the context of GVHD. Understanding such mechanisms will be critical for developing innovative strategies that can control GVHD and improve quality of life for allo-HCT patients.