FOR 2599:  Tissue type 2 responses: Mechanisms of induction and regulation

• Subject Area: Medicine
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 322359157

Type 2 immune responses, defined by a dominant milieu of the cytokines IL-4, IL-5 and IL-13, are mounted in response to helminthic parasites, hematophagous ectoparasites (e.g. ticks) and venoms. Defense against these challenges, however, may not represent the original functions of type 2 immunity since these responses have been increasingly linked with tissue repair and regeneration, metabolic homeostasis and cold adaptation. Our proposal aims to elucidate the fundamental mechanisms that induce and regulate type 2 immunity in normal tissues and in pathologies where type 2 immunity is required for protection, or is itself the driver of disease.The term ‘type 2 response’ embraces both the innate type 2 response of tissues and the adaptive TH2 and IgE responses. While adaptive TH2 and IgE-mediated immunity have been extensively studied, the rules that govern the polarization of innate responses of the different tissues remain unclear. However, it is these innate tissue responses, which educate emigrating dendritic cells, and thereby dictate the class of adaptive response (e.g. TH1, TH2 or TH17) initiated in tissue-draining lymphatic organs. Why tissues mount type 2 responses to particular challenges, but not to others, is incompletely understood, but at the same time, one of the most urgent questions in current medical research because unbalanced type 2 immune responses are central pathogenic events in atopic and fibrotic diseases. Elucidating control pathways of innate type 2 tissue responses is key to unravel causes of inappropriate IgE production in allergic diseases, as well as to understanding type 2 immunity in pathogen defense, fibrotic and metabolic disease. Insight into control of type 2 responses of tissues is required to understand how tissues repair and regenerate under the influence of tissue-specific protective immune responses.By our collaborative approach, we hope to make a major contribution to understanding how the various tissue cells interact to mount and regulate a local type 2 response in steady state or under conditions of tissue stress of different nature and intensity.

• DFG Programme: Research Units
• International Connection: Switzerland

Projects

• Age-dependent signals driving dendritic cells to promote type II immunity (Applicant Schraml-Schotta, Ph.D., Barbara )
• Alternative macrophage activation in the intestinal response to infection (Applicant Lämmermann, Ph.D., Tim )
• Alveolar macrophage self-renewal and type 2 immune response in lung injury (Applicant Sieweke, Michael )
• Control of high-affinity IgE responses to animal venoms by skin innate type 2 immunity (Applicants Jessberger, Rolf ;  Roers, Axel )
• Coordination (Applicant Roers, Axel )
• Crosstalk between Foxp3+ Regulatory T Cells and Type 2 Immunity in Maintaining Adipose Tissue Homeostasis (Applicants Chatzigeorgiou, Antonios ;  Kretschmer, Karsten )
• Differentiation of group 2 innate lymphoid cells and their role during homeostasis and type 2 inflammation (Applicants Diefenbach, Andreas ;  Klose, Christoph Siegfried Niki )
• Macrophage-intrinsic regulators of tissue type 2 inflammation (Applicants Esser-von Bieren, Julia ;  Ohnmacht, Ph.D., Caspar )
• Regulation of type 2 immunity mediated at the level of macrophage polarization (Applicant Murray, Peter J. )
• Regulators of type 2 immunity in tissue regeneration (Applicant Eming, Sabine )
• Service project: Single cell transcriptional profiling and bioinformatics (Applicants Dahl, Andreas ;  Roers, Axel )
• Tissue recruitment of type 2 effector cells (Applicant Vöhringer, David )

• Spokesperson: Professor Dr. Axel Roers