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:
  • 金额:
    $ 71.5万
  • 依托单位:
  • 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

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。

项目成果

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Mandy L Ford其他文献

Mandy L Ford的其他文献

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{{ truncateString('Mandy L Ford', 18)}}的其他基金

Nanotechnology Targeting Novel CD154:CD11b Interactions for Transplant Tolerance
纳米技术靶向新型 CD154:CD11b 相互作用以提高移植耐受性
  • 批准号:
    10622211
  • 财政年份:
    2023
  • 资助金额:
    $ 71.5万
  • 项目类别:
Determinants of T Cell Fate in Transplantation Tolerance
移植耐受中 T 细胞命运的决定因素
  • 批准号:
    10672382
  • 财政年份:
    2022
  • 资助金额:
    $ 71.5万
  • 项目类别:
CD11b: A Novel Alternate Receptor for CD154 during Alloimmunity
CD11b:同种免疫期间 CD154 的新型替代受体
  • 批准号:
    10571694
  • 财政年份:
    2020
  • 资助金额:
    $ 71.5万
  • 项目类别:
CD11b: A Novel Alternate Receptor for CD154 during Alloimmunity
CD11b:同种免疫期间 CD154 的新型替代受体
  • 批准号:
    10666184
  • 财政年份:
    2020
  • 资助金额:
    $ 71.5万
  • 项目类别:
Role of TIGIT Signaling in Transplantation
TIGIT 信号传导在移植中的作用
  • 批准号:
    10228813
  • 财政年份:
    2020
  • 资助金额:
    $ 71.5万
  • 项目类别:
CD11b: A Novel Alternate Receptor for CD154 during Alloimmunity
CD11b:同种免疫期间 CD154 的新型替代受体
  • 批准号:
    10356115
  • 财政年份:
    2020
  • 资助金额:
    $ 71.5万
  • 项目类别:
CD11b: A Novel Alternate Receptor for CD154 during Alloimmunity
CD11b:同种免疫期间 CD154 的新型替代受体
  • 批准号:
    10728916
  • 财政年份:
    2020
  • 资助金额:
    $ 71.5万
  • 项目类别:
Memory T Cell Cosigning Pathways in Sepsis-Induced Immune Dysregulation
脓毒症引起的免疫失调中的记忆 T 细胞协同信号通路
  • 批准号:
    10079469
  • 财政年份:
    2015
  • 资助金额:
    $ 71.5万
  • 项目类别:
Memory T Cell Cosigning Pathways in Sepsis-Induced Immune Dysregulation
脓毒症引起的免疫失调中的记忆 T 细胞协同信号通路
  • 批准号:
    9887580
  • 财政年份:
    2015
  • 资助金额:
    $ 71.5万
  • 项目类别:
Memory T Cell Cosigning Pathways in Sepsis-Induced Immune Dysregulation
脓毒症引起的免疫失调中的记忆 T 细胞协同信号通路
  • 批准号:
    10323009
  • 财政年份:
    2015
  • 资助金额:
    $ 71.5万
  • 项目类别:

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