IRF4-dependent T-cell effector programs in governing transplant outcomes

IRF4 依赖性 T 细胞效应程序控制移植结果

• 批准号: 9593564
• 负责人: Wenhao Chen
• 金额: $ 40.38万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9593564
• 关键词: Adverse effects; Affect; Alloantigen; Allogenic; Allografting; Binding; CD4 Positive T Lymphocytes; Cell Death; Cell Transplants; Cell physiology; Cells; Chromatin; Clinical; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Effector Cell; Enhancers; Epigenetic Process; Expression Profiling; Functional disorder; Gene Expression; Genes; Genetic Transcription; Graft Rejection; Hematopoietic; IRF4 gene; Immune; Immunity; Immunosuppression; Knock-out; Knockout Mice; MAP2K1 gene; Mediating; Modeling; Mus; Organ Transplantation; Outcome; PDCD1LG1 gene; PLAGL1 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Publications; Regulatory Element; Regulatory T-Lymphocyte; Role; SLEB2 gene; Signal Transduction; Skin graft; Solid; T cell regulation; T cell response; T-Cell Activation; T-Lymphocyte; Therapeutic immunosuppression; Transcriptional Regulation; Transplantation; base; end-stage organ failure; epigenetic regulation; genome editing; graft function; heart allograft; immune checkpoint blockade; in vivo; insight; programs; response; success; transcription factor; transplant model

Project Summary Solid organ transplantation is a lifesaving treatment for patients with end-stage organ failure, but long- term allograft survival is limited by immune rejection and side effects of immunosuppressive drugs. Allogeneic T cell responses are central to transplant outcomes (rejection versus tolerance). It is thus essential to define the T cell effector programs that affect the transplant outcomes. We recently discovered that interferon regulatory factor 4 (IRF4) is a key transcriptional determinant controlling allogenic T cell response in transplantation. IRF4 deletion in T cells results in progressive establishment of CD4+ T cell dysfunction and long-term cardiac allograft survival. These findings have been accepted for publication in Immunity. Herein, we hypothesized that IRF4 governs transplant outcomes through controlling the core regulatory circuits of T cell function. Therefore, the central focus of this proposal is to identify the IRF4 controlled regulatory circuits in alloreactive effector T cells.

项目总结