Specificity of regulatory T cell suppression during infection

摘要 免疫学中的一个基本问题在于了解免疫系统如何建立强大的T细胞 对外来病原体的反应，同时限制对内源组织的附带损害，一种状态通常 被称为“自我与非自我歧视”。尽管许多具有自身反应性的常规T(Tconv)细胞 通过克隆删除从体内移除，大量证据表明这一过程是不完美的。 控制剩余的自身反应性Tconv细胞需要CD4+Foxp3+调节性T细胞(Treg)的抑制 细胞，它们在整个生命中起着防止自身免疫的作用。努力定义Treg通过哪些机制 细胞抑制Tconv细胞已经揭示了许多潜在的机制，包括掩蔽co- 刺激配体，抑制性细胞因子的局部产生，或关键辅助因子的囤积。 然而，这些抗原非特异性“旁观者”机制不足以解释自我与非我。 歧视，特别是在感染期间先天免疫激活的情况下，突出了 研究Treg介导的抑制机制的新研究的重要性。此前，我们 鉴定出两种可被自然产生的Treg细胞识别的自体多肽(C4和F1) 它们是由单一的前列腺特异性蛋白Taf3产生的。在这里，我们将演示该选择 在曲谱形成过程中对C4肽的研究对于预防前列腺炎至关重要，而多克隆Treg 其他特性的细胞不能补偿C4特异性T细胞池的变化。这揭示了一个关键角色 用于Treg介导的匹配肽/MHC-II(pMHC-II)特异性的Tconv细胞的抑制，而不是 广泛的抗原性非特异性机制。本申请的目的是通过以下方式阐明机制 在稳态和感染期间，哪些Treg细胞协调pMHC-II特异性免疫抑制。我们会 与高级成像技术专家Ron Germain博士密切合作，实现我们的目标， 还有南希·弗雷塔格博士，他是单核细胞增生性李斯特菌(Listeria monucetogenicListeria，简称LM)的遗传学专家。在目标1中，我们 将利用功能实验和先进的共聚焦成像来确定pMHC-II的机制基础- 在稳定状态下特异性Treg细胞抑制，测试Treg细胞的假设并不阻止初始 激活pMHC-II匹配的Tconv细胞，但取而代之的是对激活的Tconv细胞做出抗流变反应 限制了他们随后的分化和扩张。在目标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辨别的特异性，检验了稳健的假设 自选Treg细胞对pMHC-II的特异性抑制由定量(数值) 感染前识别外周血自体配体的优势和定性特性。在……里面 总之，我们的工作有望阐明免疫系统协调宿主防御的关键机制 同时限制对自身组织的附带损害。

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.