Specificity of regulatory T cell suppression during infection

摘要 免疫学中的一个基本问题在于理解免疫系统如何能够建立强大的T细胞 对外来病原体的反应，同时限制对内源性组织的附带损害，这种状态通常 被称为“自我与非自我歧视”。尽管许多自身反应性常规T（Tconv）细胞是 通过克隆删除从身体中移除，大量证据表明该过程是不完美的。 剩余的自身反应性Tconv细胞的控制需要通过CD 4 + Foxp 3+调节性T（Treg）抑制 细胞，其功能贯穿整个生命，以防止自身免疫。努力定义Treg 细胞抑制Tconv细胞已经揭示了许多潜在的机制，包括掩蔽共- 刺激性配体、抑制性细胞因子的局部产生或关键辅助因子的囤积。 然而，这些抗原非特异性的“旁观者”机制不足以解释自我与非自我。 歧视，特别是在感染期间先天免疫激活的背景下，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 鉴定了两种自身肽（“C4”和“F1”肽），其被天然存在的Treg细胞识别 群体，并来自一个单一的前列腺特异性蛋白，Tcaf 3。在这里，我们证明了选择 C4肽的表达对于预防前列腺炎至关重要，多克隆Treg 其它特异性的细胞不能补偿C4特异性T细胞库中的移位。这揭示了一个关键作用 对于匹配肽/MHC-II（pMHC-II）特异性的Treg介导的Tconv细胞抑制，与 广泛的抗原非特异性机制。本申请的目的是通过以下方式阐明机制： 该Treg细胞在稳态和感染期间协调pMHC-II特异性免疫抑制。我们将 通过与高级成像技术专家罗恩杰曼博士的密切合作， 以及Nancy Freitag博士，一位单核细胞增生李斯特菌（Lm）的遗传学专家。目标1： 将使用功能实验和先进的共聚焦成像来定义pMHC-II的机制基础， 稳定状态下的特异性Treg细胞抑制，检验Treg细胞不阻止初始Treg细胞抑制的假设。 pMHC-II-匹配的Tconv细胞的激活，而是对激活的Tconv细胞的流变性应答， 限制了它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感染期间协调自我与非自我区分的特异性，测试了鲁棒性的假设。 通过自身选择的Treg细胞的pMHC-II特异性抑制是通过定量（数值） 优势和定性性质诱导的识别外周自身配体感染前。在 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.