Control of regulatory T cell homeostasis and function by Notch signaling

 描述(由申请人提供)：表达转录因子Foxp3的调节性T(Tr)细胞在外周免疫耐受和抑制旺盛的免疫反应中发挥必要的作用。阐明控制TR细胞反应的机制对于恢复慢性炎症和自身免疫疾病的耐受性至关重要。与这一目标相关的是我们最近确定的Notch通路在调节外周TR细胞室中的关键作用。转录因子受体细胞特异性表达Notch1胞内区(Notch1c)导致淋巴细胞增殖、Th1细胞因子失调和自身免疫。这些变化反映在TR细胞转录组的改变上，几个关键的TR细胞标志物的表达减少，并且在体外和体内都降低了TR细胞的抑制功能。相反，损伤Notch信号的TR特异性功能突变，包括Pofut1、Rbpj和Notch1的缺失，导致外周T细胞室收缩和Th1反应抑制。在TR细胞中，Notch信号的一些作用涉及到通过典型的Notch途径辅助因子RBPJ进行转录激活。另一些似乎涉及非规范的mTORC2/AKT/Foxo1通路的激活，表现为mTORC2靶标AKT S473的磷酸化增强，以及TCR/CD3激活时Foxo1移位到胞浆中。因此，我们假设Notch信号在可逆地调节TR细胞反应以确保最佳免疫稳态方面发挥着重要的生理功能。该通路的过度激活会导致TR细胞功能障碍、炎症和自身免疫。因此，我们建议建立tr细胞中Notch信号的生理功能，包括它在初级免疫反应中对tr细胞活动的调节，它在tr信号转导中的作用。 细胞适合性，以及相互作用的配体的身份。我们还建议通过Notch信号来确定规范和非规范转录机制在TR细胞调控中的作用。最后，我们将阐明Notch1c介导的tr细胞Th1重编程对其控制Th1反应的影响，以及Notch1c颠覆T滤泡调节(TFR)细胞的作用是促进调节失调的体液自身免疫。拟议的研究将确定涉及Notch途径的新机制，这些机制控制着TR细胞的反应，以及它们破坏培养自身免疫的后果。

 DESCRIPTION (provided by applicant): Regulatory T (TR) cells that express the transcription factor Foxp3 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 constitutive expression of the intracellular domain of Notch1 (Notch1c) led to lymphoproliferation Th1 cytokine dysregulation and autoimmunity. These changes were reflected in alterations in the TR cell transcriptome, with reduced expression of several key TR cell markers, and decreased TR cell suppressive functions both in vitro and in vivo. In contrast, TR-specific loss of function mutations that impair Notch signaling, including the deletion of Pofut1, Rbpj and Notch1, led to the contraction of the peripheral T cell compartment and suppression of Th1 response. 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 mTORC2/AKT/Foxo1 pathway, evidenced by enhanced phosphorylation of the mTORC2 target AKT S473 and augmented translocation of Foxo1 to the cytosol upon TCR/CD3 activation. Accordingly, we hypothesize that Notch signaling fulfills an important physiological function in reversibly regulating TR cell responses to ensure optimal immune homeostasis. Excessive activation of this pathway would result in TR cell dysfunction, inflammation and autoimmunity. Accordingly, we propose to establish the physiological functions of Notch signaling in TR cells, including its regulation of TR cell activity in primary immune responses, its role in conferring TR cell fitness, and the identity of the interacting ligands. We also propose to determine the contribution of canonical and non- canonical transcriptional mechanisms to TR cell regulation by Notch signaling. Finally, we will elucidate the consequences of Notch1c-mediated Th1 reprogramming of TR cells on their control of Th1 responses, and the role of T follicular regulatory (TFR) cell subversion by Notch1c is fostering dysregulated humoral autoimmunity. The proposed studies will identify novel mechanisms involving the Notch pathway that control the TR cell response and the consequence of their disruption in fostering autoimmunity.