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

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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.