TRR 355: Heterogeneity and functional specialization of regulatory T cells in distinct microenvironments

Foxp3+调节性T(Treg)细胞是CD4+T细胞的一个亚型，被认为是免疫反应的重要调节者。Treg细胞的缺乏或功能缺陷会导致自身免疫，而过度的Treg细胞反应可能会在肿瘤环境中削弱针对新自身抗原的生产性免疫反应，或在宿主防御中针对外来抗原的生产性免疫反应。最近，有一点变得很清楚，Treg细胞深度整合到许多非淋巴组织的功能结构中，并辅助可能仅间接与其免疫功能相关的功能。尽管Treg细胞在身份上有共同点，但根据它们所处的利基环境，Treg细胞正在出现微妙的异质性。只有通过了解Treg细胞的这种异质性和功能特化，才有可能设计Treg细胞靶向干预策略，不仅重建免疫稳态，而且促进再生和调节不同组织的重塑。Treg细胞异质性是如何发展以及如何维持的，例如Treg细胞的器官特异性表型和功能属性是来自循环Treg细胞池的选择性募集还是局部印迹，目前尚不清楚。在分子水平上，需要探索Treg细胞异质性的驱动力，例如表观遗传、转录或转录后机制，以确定在给定组织背景下Treg细胞异质性发展和维持的关键事件。在此背景下，TRR 355旨在以全新的视角看待Treg细胞作为高度异质性和上下文特定的免疫调节器和组织稳态的控制器。Treg细胞异质性和功能特化的条件和后果将在各种组织和疾病特定的环境中进行探索，包括运动和损伤期间肌肉驻留的Treg细胞，血栓中的Treg细胞，肺组织中的过敏原特异性Treg细胞，肠道中的Treg细胞，以及慢性炎症中的CNS驻留的Treg细胞。总而言之，TRR355将进行协调一致的努力，旨在确定可能有资格作为介入方法的目标进行进一步验证的器官特异性和疾病特异性分子或过程。随着对Treg细胞异质性和组织特定功能的深入了解，Treg细胞驱动的治疗干预的全部潜力可以实现：除了利用Treg细胞预防和调节(自身)免疫反应和慢性炎症的传统想法之外，我们认为是时候重新思考Treg细胞生物学，以开发针对器官再生和恢复组织动态平衡的定制免疫疗法。

Foxp3+ regulatory T (Treg) cells are a subtype of CD4+ T cells considered crucial modifiers of immune responses. Lack or functional deficiencies of Treg cells result in autoimmunity while exaggerated Treg cell responses may impair productive immune responses against neo-autoantigens in tumor settings or against foreign antigens in host defense. More recently, it has become clear that Treg cells are deeply integrated into the functional architecture of many non-lymphoid tissues and subserve functions that may only indirectly be linked to their immune functions. Despite commonalities in their identity, Treg cells are emerging to be exquisitely heterogeneous depending on the niche they reside in. Only through the understanding of this heterogeneity and functional specialization of Treg cells will it be possible to design strategies for Treg cell targeted interventions not only to re-establish immune homeostasis but also to facilitate regeneration and modulate remodeling of distinct tissues.It is unclear how Treg cell heterogeneity develops and how it is maintained, e.g. whether organ-specific phenotypes and functional attributes of Treg cells result from selective recruitment from the circulating Treg cell pool or from local imprinting. On a molecular level, the driving forces of Treg cell heterogeneity, e.g. epigenetic, transcriptional or post-transcriptional mechanisms, need to be explored in order to identify the key events for the development and maintenance of Treg cell heterogeneity in a given tissue context. Against this background, the TRR 355 aims to take a fresh look at Treg cells as highly heterogeneous and context-specific immune modulators and controllers of tissue homeostasis.The conditions and consequences of Treg cell heterogeneity and functional specialization will be explored in a variety of tissue- and disease-specific contexts, including muscle residing Treg cells during exercise and injury, Treg cells in blood clots, allergen specific Treg cells in lung tissue, Treg cells in the gut, and CNS-resident Treg cells in chronic inflammation. In sum, the TRR 355 will pursue a concerted effort that aims to identify organ-specific and disease-specific molecules or processes that might qualify for further validation as targets for interventional approaches. With a deeper understanding of Treg cell heterogeneity and tissue specific function, the full potential of Treg cell-driven therapeutic intervention can be achieved: Beyond the conventional ideas of harnessing Treg cells for the prevention and modulation of (auto)immune reactions and chronic inflammation, we believe that it is time to re-think Treg cell biology for the development of tailored immune therapies that also target organ regeneration and restore tissue homeostasis.