Regulatory T Cells and Th17 Cells in Autoimmune Brain Inflammation

自身免疫性脑炎症中的调节性 T 细胞和 Th17 细胞

• 批准号: 246815631
• 负责人: Professor Dr. Ari Waisman
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/246815631?language=en
• 关键词: Regulatory; Cells; Th17; Autoimmune; Brain

Immune responses are always a balance between effector and regulatory cells, which determine the extent and duration of the response. Two important cell types involved in immune responses in general, and autoimmune responses in particular, are regulatory (Tregs) and IL-17-producing CD4+ T cells (Th17). Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), and is modeled in mice by a disease termed experimental autoimmune encephalomyelitis (EAE). It was shown previously that depletion of Treg cells results in excessive EAE, and on the other hand, it was shown that Th17 cells are critical for the development of this disease. We generated a new mouse strain that allow the ablation and manipulation of Th17 cells. Using these mice we were able to mark and follow Th17 cells in vivo, and show their plasticity and transient nature. Further, we developed new mouse strains that allowed us to test directly the function of IL-17A in autoimmunity. We could show that although IL-17A is dispensable for the development of EAE, it was sufficient for the trigger of psoriasis-like disease in mice. To study the need for RORgt and IRF-4 for the development and stability of Th17 cells, we have obtained mice that allow for the conditional deletion of these two genes. These mice were crossed to mice that express the Cre recombinase in in all T cells or specifically in Th17 cells. We have found that mice lacking IRF-4 specifically in T cells are resistant to EAE induction, and further, that they do not develop Th17 cells. Finally, we have generated mice that overexpress the NF-kB family protein Bcl-3 in T cells. Bcl-3 is a transcriptional transactivator that binds p50/p52 heterodimers and homodimers. Our overexpressing mice show defects in T cell activation and spontaneous development of colitis.In the current application we plan to study the molecular requirements for the development and maintenance of Th17 cells. We will study how the deletion of RORgt and IRF-4 in all T cells or specifically in Th17 cells impact on the pathogenicity of these cells and their plasticity towards Th1 or Treg cells. This will be done using the conditional KO mice for these two transcriptional factors crossed to mice that express the Cre-recombinase in all T cells or specifically in Th17 cells. We will use mice that allow cell fate marking and follow the fate of Th17 cells once they lose the expression of these transcription factors, in a mouse model of CNS inflammation. Further more, we will use the above-mentioned new models to manipulate Bcl-3 expression in T cells and study the importance of this molecule for the development of Th17 and Treg cells. For that, we will overexpress Bcl-3 in all T cells or specifically in Th17 cells and follow the course of EAE in these mice. Together, these studies will help us to better understand the pathogenicity of Th17 cells and their lineage relationship with Th1 and Treg cells.

免疫应答总是效应细胞和调节细胞之间的平衡，这决定了应答的程度和持续时间。一般而言，参与免疫应答，特别是自身免疫应答的两种重要细胞类型是调节性（T细胞）和产生IL-17的CD 4 + T细胞（Th 17）。多发性硬化（MS）是中枢神经系统（CNS）的炎性疾病，并且通过称为实验性自身免疫性脑脊髓炎（EAE）的疾病在小鼠中建模。先前显示Treg细胞的耗尽导致过度的EAE，另一方面，显示Th 17细胞对于这种疾病的发展至关重要。我们产生了一种新的小鼠品系，允许消融和操纵Th 17细胞。使用这些小鼠，我们能够在体内标记和跟踪Th 17细胞，并显示其可塑性和瞬时性。此外，我们开发了新的小鼠品系，使我们能够直接测试IL-17 A在自身免疫中的功能。我们可以表明，虽然IL-17 A是EAE的发展，它是足够的触发银屑病样疾病的小鼠。为了研究RORgt和IRF-4对于Th 17细胞的发育和稳定性的需要，我们获得了允许条件性缺失这两种基因的小鼠。将这些小鼠与在所有T细胞中或特别是在Th 17细胞中表达Cre重组酶的小鼠杂交。我们已经发现，在T细胞中特异性缺乏IRF-4的小鼠对EAE诱导具有抗性，并且进一步地，它们不发育Th 17细胞。最后，我们已经产生了在T细胞中过表达NF-kB家族蛋白Bcl-3的小鼠。Bcl-3是结合p50/p52异二聚体和同二聚体的转录反式激活因子。我们的过表达小鼠在T细胞活化和结肠炎的自发发展中表现出缺陷。在当前的应用中，我们计划研究Th 17细胞的发展和维持的分子要求。我们将研究所有T细胞或特别是Th 17细胞中RORgt和IRF-4的缺失如何影响这些细胞的致病性及其对Th 1或Treg细胞的可塑性。这将使用这两种转录因子的条件性KO小鼠与在所有T细胞或特异性地在Th 17细胞中表达Cre重组酶的小鼠杂交来完成。我们将使用允许细胞命运标记的小鼠，并在中枢神经系统炎症小鼠模型中，一旦Th 17细胞失去这些转录因子的表达，就跟踪它们的命运。我们将利用上述新的模型来调控T细胞中Bcl-3的表达，并研究Bcl-3在Th 17和Treg细胞发育中的重要性。为此，我们将在所有T细胞或特别是Th 17细胞中过表达Bcl-3，并在这些小鼠中跟踪EAE的过程。这些研究将有助于我们更好地了解Th 17细胞的致病性及其与Th 1和Treg细胞的谱系关系。