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

调节性T细胞（Regulatory T, Treg）是一种罕见的具有强大免疫调节功能的免疫细胞。Treg细胞的缺失导致致死性炎症，而其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。利用Treg细胞的强大功能引起了医学界的强烈兴趣，但迄今为止，这样做的努力令人失望——利用Treg细胞治疗疾病仍然是该领域的一个主要突出挑战。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细胞的输出减少，但随着年龄的增长，Treg种群仍保持不变。Treg反应的维持对免疫调节记忆也至关重要，它限制了反复暴露于过敏原和感染以及Treg细胞治疗时的有害免疫反应。我们目前缺乏一个框架来理解Treg反应是如何维持的，尽管它们的免疫调节功能是持续需要的。在许多组织中，细胞群是由静止的干细胞维持的，这些干细胞自我更新，同时产生寿命较短的后代。我们最近发现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。通过对自身免疫性糖尿病和神经炎症期间炎症反应的分析，本研究将验证长寿Treg反应是分层组织的假设，即静止的自我更新祖细胞会产生寿命较短的功能活跃后代（Aim 1）。我们将定义静止细胞维持的分子机制，以及如何操纵这些机制来改善治疗（目的2）。通过重新定义我们对Treg反应的看法，我们将把重点从活化的Treg细胞转移到它们的长寿祖细胞上，对它们的治疗利用将使患有炎症性疾病、移植和癌症的患者受益。

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.