Determinants of T Cell Fate in Transplantation Tolerance

移植耐受中 T 细胞命运的决定因素

基本信息

批准号：
10672382
负责人：
Mandy L Ford
金额：
$ 71.5万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672382
关键词：
Acceleration Acute Address Antibodies Apoptosis Attenuated Automobile Driving B-Lymphocytes CASP3 gene CD8-Positive T-Lymphocytes CD8B1 gene Cell Death Cell Separation Cells Clinical Clinical Trials Data Development Enzymes Equilibrium Exhibits Experimental Models FOXP3 gene Fc Receptor Fibrinogen Freedom Funding Gangliosides Gene Expression Profiling Goals Graft Rejection Grant Human Immune Immune system Immunity Immunologics Immunosuppression Immunotherapy Induction of Apoptosis Kidney Transplantation Knowledge Life Ligands Ligation Measures Mediating Memory Messenger RNA Metabolic Metabolism Modeling Molecular Mus Organ Organ Transplantation Outcome Paper Pathway interactions Patients Peripheral Blood Mononuclear Cell Play Proteins Proteomics Receptor Signaling Regulation Regulatory Pathway Regulatory T-Lymphocyte Resistance Role Seminal Series Signal Pathway Signal Transduction Signaling Molecule Source Surface T cell response T memory cell T-Cell Activation T-Lymphocyte Tacrolimus Testing Therapeutic Therapeutic Intervention Transplant Recipients Transplantation Transplantation Tolerance Validation Waiting Lists Weaning allograft rejection clinically relevant cohort cytokine end-stage organ failure experimental study immune activation immunoregulation improved outcome in vivo isoimmunity kidney allograft mouse model nonhuman primate novel novel therapeutics patient population predictive marker receptor response retransplantation risk stratification skin allograft transcriptome sequencing translational study

项目摘要

Transplantation is a cure for end stage organ failure, yet achieving “one transplant for life” remains elusive for many transplant recipients due to immunologic rejection. Studies in mouse and NHP models and patient populations have consistently implicated memory CD8+ T cells as playing a causal role in mediating immunosuppression-resistant allograft rejection. Thus, the identification of the molecular mechanisms that regulate memory CD8+ T cells responses remains an important goal for immunotherapy in clinical transplantation. Fc receptors, previously known only to be expressed on B cells and innate immune cells, can fine-tune immune cell activation based on the balance of activating and inhibitory Fc receptor signaling, much like T cell costimulatory and coinhibitory molecules. During the last funding cycle we identified that the inhibitory receptor FcγRIIB is also expressed on a subset of multi-functional effector/ memory CD8+ T cells in mice and in humans, and showed that FcγRIIB functionally regulates CD8+ T cell immunity in a cell- autonomous manner in both mice and in a human clinical trial. However, the mechanisms by which this occurs are still not clear. First, the signals via which FcγRIIB ligation leads to T cell death are not known. We discovered that FcγRIIB signaling on CD8+ T cells is not controlled by antibody ligation, but instead by a novel immunosuppressive cytokine fibrinogen-like 2 (Fgl2). Moreover, our additional preliminary data suggest a FcγRIIB SHIP1-dependent mechanism that leads to the induction of apoptosis. Thus, in Aim 1, we will determine the cellular source of Fgl2 that is critical for FcγRIIB-mediated CD8+ T cell apoptosis, and will use a proteomics approach to elucidate the proximal intracellular signaling molecules that associate with FcγRIIB to promote caspase 3/7 activity. Second, we made the novel observation that FcγRIIB+ CD8+ T cells exhibit increased expression of the ganglioside metabolic enzyme Gm2a, and that increased expression of Gm2a mRNA in CD8+ T cells is associated with stability on minimal immunosuppression in a cohort of human renal transplant recipients. These preliminary data form the premise for the hypothesis to be tested in Aim 2: that Gm2a is a novel regulatory pathway that regulates transplant acceptance, potentially in an FcγRIIB- dependent fashion. Finally, in Aim 3 we propose to directly measure FcγRIIB, Fgl2, and Gm2a expression in CD8+ T cells isolated from a validation cohort of human renal transplant recipients, and to determine the association between CD8+ T cell FcγRIIB and Gm2a expression and reduced alloimmunity and/or acute rejection. These data will allow us to determine the ability of FcγRIIB/Gm2a-expressing T cells to be used as a predictive biomarker to stratify the risk of rejection following transplantation. In sum, through these mechanistic and translational studies, we will elucidate the fundamental molecular and cellular pathways of FcγRIIB- mediated inhibition of CD8+ T cell responses, and their therapeutic potential to attenuate memory CD8+ T cell responses and improve outcomes in clinical transplantation.

移植是治愈末端器官衰竭的方法，但是实现“生命的一个移植”仍然难以捉摸由于免疫排斥，许多移植受者。对小鼠和NHP模型以及患者的研究人群一直在内存中实现记忆CD8+ T细胞在中介中起因果的作用免疫抑制的同种异体成形术排斥。那是分子机制的鉴定调节记忆CD8+ T细胞反应仍然是临床免疫疗法的重要目标移植。 FC受体以前已知仅在B细胞和先天免疫细胞上表达，可以基于激活和抑制性FC受体信号的平衡，微调免疫细胞激活，很多例如T细胞的共刺激和共抑制分子。在上一个资金周期中，我们确定了抑制性受体FcγRIIB也在多功能效应子/记忆CD8+ T细胞的子集中表达小鼠和人类中，表明FcγRIIB在细胞中调节CD8+ T细胞的免疫力在小鼠和人类临床试验中，自主方式。但是，发生这种情况的机制仍然不清楚。首先，FcγRIIB连接导致T细胞死亡的信号尚不清楚。我们发现CD8+ T细胞上的FcγRIIB信号传导不受抗体连接的控制，而是通过新颖的免疫抑制细胞因子纤维蛋白原样2（FGL2）。此外，我们的其他初步数据表明 FcγRIIB船舶1依赖性机制，导致凋亡的诱导。在AIM 1中，我们将确定对FcγRIIB介导的CD8+ T细胞凋亡至关重要的FGL2的细胞来源将使用蛋白质组学方法来阐明与之相关的近端细胞内信号分子 FcγRIIB促进caspase 3/7活性。其次，我们对FcγRIIB+ CD8+ T细胞进行了新的观察结果表现出增加的神经节苷脂代谢酶GM2A的表达增加，并增加 CD8+ T细胞中的GM2A mRNA与人类队列中最小免疫抑制的稳定性有关肾移植受者。这些初步数据构成了在AIM 2中进行检验的假设的前提： GM2A是一种新型的调节途径，可调节移植接受，可能在FcγRiib- 依赖的时尚。最后，在AIM 3中，我们建议直接测量FcγRIIB，FGL2和GM2A表达从人类肾移植受者的验证队列中分离出的CD8+ T细胞，并确定 CD8+ T细胞FcγRIIB和GM2A表达之间的关联，并降低同种免疫力和/或急性拒绝。这些数据将使我们能够确定FcγRIIB/表达T细胞的能力预测性生物标志物可以分层移植后排斥的风险。总而言之并翻译了研究，我们将阐明FcγRIIB-的基本分子和细胞途径介导的CD8+ T细胞反应的抑制作用及其减弱记忆CD8+ T细胞的治疗潜力反应和改善临床移植的结果。