IMMUNOREG: Memory of Self: Maintenance and memory of immunoregulatory responses

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细胞的丧失会导致致命性炎症，而它们的功能缺陷与自身免疫和过敏有关。Treg细胞也抑制癌症的免疫反应。人们对开发Treg细胞的强大功能有着浓厚的医学兴趣，但到目前为止，这样做的努力一直令人失望-利用Treg细胞治疗疾病仍然是该领域面临的主要突出挑战。为了正常工作，Treg反应需要长期存在：在生命早期发育的Treg细胞需要在整个生命中持续发挥作用，以防止致命的炎症。尽管胸腺新T细胞的产量减少，但Treg群体随着我们的年龄增长而保持不变。Treg反应的维持对免疫调节记忆和Treg细胞治疗也是至关重要的，免疫调节记忆可限制反复暴露于过敏原和感染时的有害免疫反应。我们目前缺乏一个框架来理解Treg反应是如何维持的，尽管对它们的免疫调节功能有持续的要求。在许多组织中，细胞群体由静止的干细胞维持，干细胞自我更新，同时产生寿命较短的后代。我们最近发现，干细胞的一个关键特征-静止-需要Treg细胞长时间保持。这项研究将集中我们对自身免疫性糖尿病和神经炎症期间炎症反应的分析，这项研究将检验这样一种假设，即长期存活的Treg反应是分级组织的，静止的自我更新的祖细胞产生较短寿命的功能活跃的后代(目标1)。我们将定义维持静止细胞的分子机制，以及如何操纵这些机制来改进治疗(目标2)。通过重新定义我们对Treg反应的看法，我们将把重点从激活的Treg细胞转移到它们的长寿祖细胞上，这些祖细胞的治疗将使炎症性疾病、移植和癌症患者受益。

Regulatory T (Treg) cells are rare immune cells with powerful immunoregulatory functions. Loss of Treg cells results in lethal inflammation, while defects in their function are associated with autoimmunity and allergy. Treg cells also suppress immune responses in cancer. There is intense medical interest in exploiting the powerful functions of Treg cells but efforts to do so have thus far been disappointing - harnessing Treg cells to treat disease remains a major outstanding challenge for the field.To work properly, Treg responses need to be long-lived: Treg cells that develop early in life need to function continuously throughout life to prevent lethal inflammation. Treg populations are maintained as we age despite reduced thymic output of new T cells. Maintenance of Treg responses is also critical to immunoregulatory memory, which limits harmful immune reactions upon repeated exposure to allergens and infection, and to Treg cell therapy. We presently lack a framework for understanding how Treg responses are maintained despite a continuous requirement for their immunoregulatory functions. In many tissues, cell populations are maintained by quiescent stem cells which self-renew while giving rise to shorter-lived progeny. We have recently found that a critical characteristic of stem cells - quiescence - is required for Treg cells to be maintained over long periods of time.Focussing our analyses on inflammatory responses during autoimmune diabetes and neuroinflammation, this research 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 (Aim 1). We will define molecular mechanisms by which quiescent cells are maintained and how these can be manipulated to improve therapy (Aim 2). By redefining how we think about Treg responses, we will shift the focus from activated Treg cells to their long-lived progenitors whose therapeutic harnessing will benefit patients with inflammatory diseases, transplantation and cancer.