CD27/CD70 mediated negative regulation of inflammatory T cell responses

CD27/CD70 介导的炎症 T 细胞反应的负调节

• 批准号: 9523419
• 负责人: Xuefang Cao
• 金额: $ 58.61万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9523419
• 关键词: Affect; Allogenic; Antibodies; Antigen-Presenting Cells; Antigens; Cell surface; Cells; Chimera organism; Complex; Complication; Exhibits; Family member; Hematological Disease; Hematopoietic; Human; ITGAX gene; Immune System Diseases; In Vitro; Incidence; Infection; Inflammatory; Lead; Ligands; Lymphocyte; MHC antigen; Mediating; Memory; Metabolism; Modeling; Morbidity - disease rate; Mus; Normal tissue morphology; Organ; Pathway interactions; Patients; Play; Quality of life; Regulation; Regulatory T-Lymphocyte; Resistance; Role; Severities; Signal Transduction; Signal Transduction Pathway; Specific qualifier value; T cell response; T-Cell Activation; T-Lymphocyte; TNFRSF1A gene; Testing; Therapeutic immunosuppression; Up-Regulation; Virus Diseases; Xenograft procedure; base; clinically relevant; curative treatments; cytokine; cytotoxic; design; exhaustion; graft vs host disease; hematopoietic cell transplantation; improved; in vivo; innovation; migration; mortality; mouse model; novel; novel strategies; overexpression; therapeutic evaluation

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.

同种异体造血细胞移植（Allo-HCT）是一种潜在的治疗方法 血液学和免疫疾病。但是，移植物与宿主病（GVHD）仍然是主要的 引起大量发病和死亡任务的并发症当前实行的免疫抑制 疗法。已知GVHD是由识别表达的同种异体抗原的供体衍生的T细胞引起的 在宿主细胞上，随后损坏宿主正常组织。除了由MHC-刺激的TCR信号传导 抗原复合物，共刺激途径参与T细胞激活和功能。联合刺激 分子CD27是在T细胞上表达的TNF受体家族成员，其配体CD70已知为 在活化的抗原呈递细胞（APC）和T细胞上表达。先前使用病毒的研究 感染模型在很大程度上将此途径描述为“刺激性”，最佳T细胞所需 反应，而其在Allo-HCT中的作用以前是未知的。在这个项目中，我们使用了已建立的鼠 研究CD27/CD70在GVHD中的作用的模型。我们的结果揭示了这种新颖的抑制作用 如两个方面所指定的途径：1）Allo-HCT表明CD27 - / - 和CD70 - / - 供体T细胞均导致更多 严重的GVHD比WT供体T细胞，表明供体T细胞中的CD27/CD70信号抑制同种异体 T细胞反应； 2）当用作Allo-HCT的宿主时，CD27 - / - 和CD70 - / - 小鼠暴露更严重 GVHD与WT宿主相比，表明宿主中的CD27/CD70信号抑制同种异体T细胞 回复。初始机械分析表明，该途径通过限制供体T细胞抑制GVHD 以供体调节性T细胞独立的方式膨胀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信号传导起着新的作用，抑制GVHD 抑制同种异体炎症T细胞反应。我们提出三个目标，以系统地追求捐助者 细胞衍生的机制，宿主衍生的机制和该途径的临床相关性 GVHD。了解这种机制对于制定可以控制的创新策略至关重要 GVHD并改善Allo-HCT患者的生活质量。