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

• Subject Area: Biology ; Medicine
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 490846870

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.

• DFG Programme: CRC/Transregios

Current projects

• A01 - Dynamics, epigenetic signatures and modulating factors of tissue Treg cell differentiation (Project Heads Delacher, Michael ;  Hühn, Jochen )
• A02 - Role and regulation of muscle-residing Foxp3+ Treg cells in health and disease (Project Head Daniel, Carolin )
• A04 - The role of cAMP in regulatory T cell homeostasis and function (Project Head Sparwasser, Tim Dominik )
• A05 - Regulation of Treg cell subsets and function by the atypical IkB protein Bcl-3 (Project Heads Hövelmeyer, Nadine ;  Ohnmacht, Ph.D., Caspar )
• A06 - Post-transcriptional control of tissue-resident regulatory T cells (Project Head Heissmeyer, Vigo )
• A07 - Investigating Treg cell plasticity in mice and man (Project Heads Schmidt-Supprian, Marc ;  Schumann, Kathrin )
• A08 - The role of non-canonical NF-κB signaling in Treg cells in tissue homeostasis and disease (Project Heads Kramer, Daniela ;  Waisman, Ari )
• A09 - CK2 as a Molecular Switch Regulating Immunity and Tolerance by APC-dependent Induction of Treg cells (Project Heads Bopp, Tobias ;  Clausen, Björn )
• A10 - Myeloid cell–regulatory T cell crosstalk in thrombus development and resolution (Project Heads Bopp, Tobias ;  Ruf, Wolfram )
• B01 - Inter- and intramolecular cross-regulation during CNS autoimmunity (Project Head Klein, Ludger )
• B02 - Impact of CCR4 ligands on tissue Treg cells in islet autoimmunity (Project Heads Anz, David ;  Serr, Isabelle )
• B03 - Induction of Antigen-specific Treg responses as therapeutic targets for chronic inflammatory diseases (Project Heads Bacher, Petra ;  Scheffold, Alexander )
• B04 - Microbiota-induced intestinal Treg cells modulate neuroinflammation (Project Heads Benakis, Corinne ;  Regen, Tommy )
• B05 - In situ reprogramming of dendritic cells for immunomodulation of CNS-specific Foxp3+ regulatory T cells (Project Heads Sahin, Ugur ;  Waisman, Ari )
• B06 - Disease-overarching mechanisms of Treg-CNS interaction (Project Heads Bittner, Stefan ;  Liesz, Arthur )
• B07 - Treg cells in the chronically inflamed CNS (Project Heads Korn, Thomas ;  Muschaweckh, Andreas )
• B08 - Treg cells as modulators of gluten-induced inflammation in celiac disease (Project Heads Berod, Ph.D., Luciana ;  Schuppan, Detlef )
• B09 - Tissue-derived eicosanoids as modulators of Treg cell induction, stability and function (Project Heads Esser-von Bieren, Julia ;  Prazeres da Costa, Clarissa )
• MGK - Integrated Research Training Group (Project Heads Berod, Ph.D., Luciana ;  Daniel, Carolin )
• Z01 - Central Tasks (Project Head Waisman, Ari )
• Z02 - Treg Commons (Project Heads Delacher, Michael ;  Schubert, Benjamin )

• Applicant Institution: Johannes Gutenberg-Universität Mainz
• Co-Applicant Institution: Ludwig-Maximilians-Universität München; Technische Universität München (TUM)
• Participating University: Christian-Albrechts-Universität zu Kiel
• Participating Institution: Helmholtz-Zentrum für Infektionsforschung (HZI); Arbeitsgruppe Experimentelle Immunologie; Helmholtz Zentrum München; Deutsches Forschungszentrum für Gesundheit und Umwelt; Institut für Computational Biology (ICB)
• Spokesperson: Professor Dr. Ari Waisman