Stemness and maintenance of CD4+ regulatory T cell (Treg) responses in homeostasis, inflammation and ageing

BBSRC战略主题：CD 4+调节性T（Treg）细胞是一种罕见的免疫细胞，具有强大的免疫调节功能。Treg细胞在整个生命周期中都是必需的，可以防止致命的炎症。其功能缺陷与自身免疫和过敏有关。人们对开发Treg细胞的强大功能有着强烈的科学和翻译兴趣，但迄今为止的努力令人失望-这表明需要更好地了解其潜在的生物学。虽然现在对Treg细胞如何发育有了很多了解，但我们缺乏对Treg反应如何维持的了解。大多数Treg细胞在生命早期发育，但在整个生命过程中需要维持Treg应答，并进入老年以促进免疫稳态。Treg应答的维持对于Treg靶向疗法（包括Treg细胞疗法和致耐受性疫苗）的功效也至关重要。在许多组织中，细胞群由静止的干细胞维持，这些干细胞自我更新，同时产生寿命较短的后代。我们最近发表的工作（格兰特等人，J Exp Med 2020）显示，干细胞的一个关键特征-静止-是Treg细胞长时间维持所必需的。使用尖端的新小鼠遗传模型，使Treg细胞亚群能够精确追踪和消除，该学生将测试长寿Treg反应是分层组织的假设，静止的自我更新祖细胞产生寿命较短的功能活性后代。它将定义静止Treg细胞维持到年龄以促进终身免疫和组织稳态的分子机制。

BBSRC strategic theme: Bioscience for an integrated understanding of healthCD4+ Regulatory T (Treg) cells are rare immune cells with powerful immunoregulatory functions. Treg cells are required throughout the lifespan prevent lethal inflammation. Defects in their function are associated with autoimmunity and allergy. There is intense scientific and translational interest in exploiting the powerful functions of Treg cells but efforts to do so have thus far been disappointing - indicating the need to develop a better understanding of their underlying biology.While much is now known about how Treg cells develop, we lack understanding of how Treg responses are maintained. A majority of Treg cells develop in early life, but maintenance of Treg responses is required throughout life and into age to promote immune homeostasis. Maintenance of Treg responses is also critical to efficacy of Treg-targeted therapies, including Treg cell therapy and tolerogenic vaccines. In many tissues, cellular populations are maintained by quiescent stem cells which self-renew while giving rise to shorter-lived progeny. Our recent published work (Grant et al., J Exp Med 2020) shows that a critical characteristic of stem cells - quiescence - is required for Treg cells to be maintained over long periods of time.Using cutting-edge new mouse genetic models which enable Treg cell subpopulations to be precisely fate-tracked and depleted, this studentship will test the hypothesis that long-lived Treg responses are hierarchically organised, with quiescent self-renewing progenitor cells giving rise to shorter-lived functionally active progeny. It will define molecular mechanisms by which quiescent Treg cells are maintained into age to promote lifelong immune and tissue homeostasis.