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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：
10539825
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/10539825
关键词：
Acute Address Antibodies Apoptosis Attenuated Automobile Driving B-Lymphocytes CASP3 gene CD8-Positive T-Lymphocytes CD8B1 gene Cell Death 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 Sum Surface T cell response T memory cell T-Cell Activation T-Lymphocyte Tacrolimus Testing Therapeutic Therapeutic Intervention Time Transplant Recipients Transplantation Transplantation Tolerance Validation Waiting Lists Weaning allograft rejection base 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 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.

移植是治疗终末期器官衰竭的一种方法，但实现“一次移植终身”仍然难以实现许多移植受者由于免疫排斥反应。小鼠和 NHP 模型及患者的研究人群一致认为记忆 CD8+ T 细胞在介导中起着因果作用免疫抑制抵抗的同种异体移植排斥反应。因此，分子机制的鉴定调节记忆CD8+ T细胞反应仍然是临床免疫治疗的重要目标移植。 Fc 受体此前已知仅在 B 细胞和先天免疫细胞上表达，但现在可以基于激活和抑制 Fc 受体信号传导的平衡来微调免疫细胞激活，如 T 细胞共刺激分子和共抑制分子。在上一个融资周期中，我们发现抑制性受体 FcγRIIB 也在多功能效应/记忆 CD8+ T 细胞亚群上表达小鼠和人类中，并表明 FcγRIIB 功能性调节细胞中的 CD8+ T 细胞免疫在小鼠和人类临床试验中以自主方式进行。然而，这种情况发生的机制仍不清楚。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 信号传导不是由抗体连接控制，而是由一种新型的免疫抑制细胞因子纤维蛋白原样 2 (Fgl2)。此外，我们的额外初步数据表明 FcγRIIB SHIP1 依赖性机制导致细胞凋亡的诱导。因此，在目标 1 中，我们将确定对 FcγRIIB 介导的 CD8+ T 细胞凋亡至关重要的 Fgl2 细胞来源，以及将使用蛋白质组学方法来阐明与相关的近端细胞内信号分子 FcγRIIB 促进 caspase 3/7 活性。其次，我们发现 FcγRIIB+ CD8+ T 细胞表现出神经节苷脂代谢酶 Gm2a 表达增加，并且 CD8+ T 细胞中的 Gm2a mRNA 与一组人类中最小免疫抑制的稳定性相关肾移植受者。这些初步数据构成了目标 2 中要检验的假设的前提： Gm2a 是一种新的调节途径，可调节移植接受，可能在 FcγRIIB- 依赖时尚。最后，在目标 3 中，我们建议直接测量 FcγRIIB、Fgl2 和 Gm2a 表达从人类肾移植受者验证队列中分离出 CD8+ T 细胞，并确定 CD8+ T 细胞 FcγRIIB 和 Gm2a 表达与同种免疫降低和/或急性拒绝。这些数据将使我们能够确定表达 FcγRIIB/Gm2a 的 T 细胞用作预测性生物标志物对移植后排斥风险进行分层。总而言之，通过这些机制和转化研究，我们将阐明 FcγRIIB- 的基本分子和细胞途径介导的 CD8+ T 细胞反应抑制及其减弱记忆 CD8+ T 细胞的治疗潜力反应并改善临床移植的结果。