Control of regulatory T cell homeostasis and function by Notch signaling

摘要 Foxp3调节性T(Tr)在外周免疫耐受和抑制中发挥必要作用 旺盛的免疫反应。阐明控制tr细胞反应的机制至关重要。 恢复对慢性炎症和自身免疫性疾病的耐受性。与这一目标相关的是 我们最近确定了Notch通路在调节外周TR细胞中的关键作用 车厢。TR细胞特异性缺失Notch1拮抗辅助性T细胞(Th)1反应并保护其免受 移植物抗宿主病，而tr细胞特异性的Notch1胞内结构域的表达 导致淋巴细胞增殖、Th1细胞失调和自身免疫。我们还证明了tr细胞- 通过所有Notch受体(Pofut1)丧失信号能力的特异性Notch途径突变 缺失)或规范通路信号(Rbpj缺失)，而不是Notch1或Notch2的缺失，受保护 过敏性气道炎，表明单个的Notch受体介导了对 独特的Th细胞程序。转录因子受体细胞中Notch信号的部分作用与转录激活有关 通过典型的Notch途径辅助因子RBPJ。还有其他的似乎涉及激活非- 正则机制。因此，我们假设Notch信号实现了一个重要的生理 在负调节tr细胞中的作用，以确保最佳免疫平衡。过度激活这个 途径会导致受体细胞功能障碍，导致免疫调节失调、炎症和自身免疫。 我们进一步假设，在控制Th的过程中，TR细胞上的单个Notch受体发挥了非冗余的作用 细胞反应，Notch1分别调节Th1和Notch4 Th2细胞反应。我们还假设 TR细胞上单个Notch受体介导不同免疫调节结果的能力是 通过Notch受体-配体的层级相互作用和由 各自的Notch受体。我们建议在目标1下阐明维持Notch1的机制 TR细胞中的信号通过使Th1细胞完全重新编程来促进失调的Th1细胞反应 以及Notch1信号对T滤泡调节(TFR)细胞的颠覆作用 体液自身免疫。在目标2下，我们将研究在TR细胞中Notch信号传递的机制，大多数 值得注意的是，Notch4(可能还有Notch3)调节过敏性呼吸道炎症中的Th2细胞反应， 而Aim 3将探索通过TR细胞中不同Notch受体的信号转导机制 不同的功能结果，包括在TR细胞上表达的各自受体的配基特异性和 下游转录程序的性质是在Notch1和Notch4信号基础上激活的。这个 拟议的研究将确定Notch信号控制与以下相关的TR细胞活动的新机制 不同的炎症模式，并将与常见的免疫调节失调疾病有关，包括 自身免疫性疾病、移植物抗宿主病和过敏性炎症，如哮喘。

Abstract Foxp3+ regulatory T (TR) play a requisite role in peripheral immunological tolerance and in restraining exuberant immune responses. Elucidating mechanisms that control TR cell responses is of pivotal importance to the restoration of tolerance in diseases of chronic inflammation and autoimmunity. Relevant to this goal is our recent determination of a critical role for the Notch pathway in regulating the peripheral TR cell compartment. TR cell-specific deletion of Notch1 antagonized T helper (Th)1 responses and protected against graft versus host disease, while TR cell-specific constitutive expression of the intracellular domain of Notch1 led to lymphoproliferation, Th1 cell dysregulation and autoimmunity. We have also demonstrated that TR cell- specific loss of function Notch pathway mutations that incapacitate signaling via all Notch receptors (Pofut1 deletion) or canonical pathway signaling (Rbpj deletion) but not deletion of Notch1 or Notch2, protected against allergic airway inflammation, indicating that individual Notch receptors on TR cells mediated regulation of distinct Th cell programs. Some of the effects of Notch signaling in TR cells involved transcriptional activation via the canonical Notch pathway co-factor RBPJ. Yet others appeared to involve activation of the non- canonical mechanisms. Accordingly, We hypothesize that Notch signaling fulfills an important physiological role in negatively regulating TR cells to ensure optimal immune homeostasis. Excessive activation of this pathway would result in TR cell dysfunction, leading to immune dysregulation, inflammation and autoimmunity. We further hypothesize that individual Notch receptors on TR cells fulfill non-redundant roles in controlling Th cell responses, with Notch1 regulating Th1 and Notch4 Th2 cell responses, respectively. We also hypothesize that the capacity of individual Notch receptors on TR cells to mediate distinct immune regulatory outcomes is reflected by hierarchal Notch receptor-ligand interactions and by distinct transcriptional circuitries activated by the respective Notch receptors. We propose under Aim 1 to elucidate mechanisms by which sustained Notch1 signaling in TR cells promotes dysregulated Th1 cell responses by enabling complete Th1 cell reprogramming of TR cells, and the role of T follicular regulatory (TFR) cell subversion by Notch1 signaling in inciting intense humoral autoimmunity. Under Aim 2, we will examine mechanisms by which Notch signaling in TR cells, most notably that by Notch4 (and possibly Notch3), regulates Th2 cell responses in allergic airway inflammation, while Aim 3 will explore mechanisms by which signaling via different Notch receptors in TR cells leads to distinct functional outcomes, including ligand specificity of the respective receptor expressed on TR cells and the nature of the downstream transcriptional programs activated upon Notch1 versus Notch4 signaling. The proposed studies will identify novel mechanisms by which Notch signaling controls TR cell activities relevant to different inflammatory paradigms, and will have bearing on common immune dysregulatory diseases, including autoimmune disorders, graft versus host disease and allergic inflammation such as in asthma.