Specificity of regulatory T cell suppression during infection

感染过程中调节性 T 细胞抑制的特异性

• 批准号: 10397705
• 负责人: Peter Aidan Savage
• 金额: $ 40.39万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397705
• 关键词: Antigens; Autoimmune Diseases; Autoimmunity; Bacteria; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Clonal Deletion; Collaborations; Complex; Compulsive Hoarding; Data; Discrimination; FOXP3 gene; Gene Targeting; Genetic; Host Defense; Image; Imaging Techniques; Immune system; Immunology; Immunosuppression; Infection; Inflammatory; Life; Ligands; Listeria monocytogenes; Magnetism; Masks; Mediating; Modality; Modeling; Mus; Peptide/MHC Complex; Peptides; Peripheral; Physiological; Population; Positioning Attribute; Prevention; Process; Production; Property; Prostate; Prostatic; Proteins; Recombinants; Regulatory T-Lymphocyte; Research; Role; Specificity; Syndrome; System; T cell response; T-Lymphocyte; Testing; Thymus Gland; Tissues; Training; Transgenic Organisms; Tumor-infiltrating immune cells; Wild Type Mouse; Work; confocal imaging; cytokine; density; experimental study; immune activation; in vivo; insight; male; pathogen; prevent; prostatitis; response; tool

ABSTRACT A fundamental question in immunology lies in understanding how the immune system can mount robust T cell responses to foreign pathogens, while restricting collateral damage to endogenous tissues, a state often referred to as "self vs. non-self discrimination". Although many self-reactive conventional T (Tconv) cells are removed from the body by clonal deletion, considerable evidence demonstrates that this process is imperfect. The control of remaining self-reactive Tconv cells requires suppression by CD4+Foxp3+ regulatory T (Treg) cells, which function throughout life to prevent autoimmunity. Efforts to define the mechanisms by which Treg cells suppress Tconv cells have revealed numerous potential mechanisms, including the masking of co- stimulatory ligands, the local production of suppressive cytokines, or the hoarding of key accessory factors. However, these antigen non-specific "bystander" mechanisms are not sufficient to explain self vs. non-self discrimination, especially in the context of innate immune activation during infection, highlighting the importance of new research examining the mechanisms of Treg-mediated suppression. Previously, we identified two self-peptides ("C4" and "F1" peptides) that are recognized by naturally occurring Treg cell populations and are derived from a single prostate-specific protein, Tcaf3. Here, we demonstrate that selection on the C4 peptide during repertoire formation is critical for the prevention of prostatitis, and that polyclonal Treg cells of other specificities can not compensate for the shift in the C4-specific T cell pool. This reveals a key role for Treg-mediated suppression of Tconv cells of matched peptide/MHC-II (pMHC-II) specificity, as opposed to broad antigen non-specific mechanisms. The objectives of this application are to elucidate mechanisms by which Treg cells coordinate pMHC-II-specific immune suppression at steady state and during infection. We will achieve our objectives in close collaboration with Dr. Ron Germain, an expert in advanced imaging techniques, and Dr. Nancy Freitag, an expert in the genetics of the bacterium Listeria monocytogenes (Lm). In Aim 1, we will use functional experiments and advanced confocal imaging to define the mechanistic basis of pMHC-II- specific Treg cell suppression at steady state, testing the hypothesis Treg cells do not prevent the initial activation of pMHC-II-matched Tconv cells, but instead rheostatically respond to activated Tconv cells to restrict their subsequent differentiation and expansion. In Aim 2, we will define the role of Treg cell pMHC-II specificity in coordinating self vs. non-self discrimination during Lm infection, testing the hypothesis that robust pMHC-II-specific suppression by self-selected Treg cells is imparted by both quantitative (numerical) advantages and qualitative properties induced by the recognition of peripheral self-ligand prior to infection. In all, our work is expected to elucidate key mechanisms by which the immune system orchestrates host defense while limiting collateral damage to self tissues.

抽象的 免疫学的一个基本问题在于了解免疫系统如何安装稳健的T细胞 对外国病原体的反应，同时限制了对内源性组织的附带损害，这​​种状态通常 称为“自我与非自我歧视”。尽管许多自我反应性常规t（TCONV）细胞是 通过克隆缺失从身体中移除，有大量证据表明该过程不完善。 剩余的自我反应性TCONV细胞的控制需要CD4+ FOXP3+调节t（Treg）抑制 细胞，这些细胞在一生中起作用，以防止自身免疫性。努力定义Treg的机制 细胞抑制TCONV细胞已经揭示了许多潜在的机制，包括掩盖共同体 刺激配体，局部抑制细胞因子的局部产生或关键辅助因子的ho积。 但是，这些抗原非特异性的“旁观者”机制不足以解释自我与非自我 歧视，尤其是在感染期间先天免疫激活的背景下 研究新研究的重要性，研究了Treg介导的抑制的机制。以前，我们 鉴定出两种自然存在的Treg细胞识别的两个自肽（“ C4”和“ F1”肽） 种群源自单个前列腺特异性蛋白TCAF3。在这里，我们证明了选择 在曲目形成过程中，在C4肽上对于预防前列腺炎至关重要，而多克隆Treg 其他特异性细胞无法补偿C4特异性T细胞池的变化。这揭示了一个关键角色 用于Treg介导的抑制匹配肽/MHC-II（PMHC-II）特异性的TCONV细胞，而不是 广泛的抗原非特异性机制。该应用程序的目标是通过 Treg细胞在稳态和感染过程中协调PMHC-II特异性免疫抑制。我们将 与高级成像技术专家Ron Germain博士密切合作实现我们的目标， Nancy Freitag博士是李斯特菌单核细胞增生菌（LM）的遗传学专家。在AIM 1中，我们 将使用功能实验和晚期共聚焦成像来定义PMHC-II的机理基础 特定的Treg细胞在稳态下抑制，测试假设Treg细胞并不能阻止初始 pMHC-II匹配的TCONV细胞的激活，但抑制了激活的TCONV细胞对 限制他们随后的差异和扩展。在AIM 2中，我们将定义Treg细胞PMHC-II的作用 在LM感染过程中协调自我与非自我歧视的特异性，检验了可靠的假设 自选择的treg细胞的PMHC-II特异性抑制均由定量（数值）赋予 在感染之前识别外周自配音引起的优势和定性特性。在 所有这些，我们的工作有望阐明免疫系统会策划主机防御的关键机制 同时限制了对自组织的附带损害。