The role of Death Receptor 3 signaling in human regulatory T cells

• Applicant: Privatdozent Dr. Martin Ehrenschwender
• Subject Area: Cell Biology ; Immunology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 282297766

Death Receptor 3 belongs like its relative Tumor-Necrosis-Factor-Receptor 1 (TNFR1) to the death receptor subgroup of the TNF-receptor family. Like TNFR1, DR3 predominately triggers proinflammatory signaling pathways following activation by its ligand TL1A. Accordingly, TNF but also TL1A are involved in a variety of processes regulating the immune system and are important players in (patho-) physiological inflammation. However, in contrast to TNFR1, which can be found on the surface of almost any cell type, constitutive DR3 expression is mainly restricted to regulatory T-cells (Tregs). Potentially, this could allow exclusive and specific targeting of this therapeutically promising T-cell subset. To date, DR3 signaling in human Tregs has not been investigated. To fulfill their function, Tregs depend on intact T-cell receptor and IL2-receptor signaling pathways. Additionally, a number of TNF-receptors are critically involved during differentiation. Given the fact that Tregs physiologically operate in a complex environment of cytokines and immune cells, Tregs encounter regularly simultaneous or sequential activation of different signaling pathways. We have previously shown that simultaneously activated receptor-ligand systems can interfere with each other (receptor crosstalk) and significantly determine the cellular response to the initial stimulus. Consequently, analyzing DR3 signaling especially in Tregs should definitely consider the possibility of receptor crosstalk. Otherwise, targeting DR3 with therapeutic intention might under some circumstances have deleterious effects. This proposal aims to investigate the role of DR3 signaling in human Tregs with special consideration of potential modulating effects through receptor crosstalk with other signaling pathways important for Treg function. In particular, receptor crosstalk between DR3 and the TNF-receptors GITR, OX40, TNFR2, CD27 and 4-1BB will be examined. Additionally, crosstalk between DR3 and the IL2-receptor, the T-cell-receptor and the Toll-like-receptors 2 and 4 will be addressed. At the molecular level, effects on the activation of proinflammatory signaling pathways, initiation of signaling complexes, cytokine secretion and viability will be assessed. Combined with the impact of receptor crosstalk on Treg function, e.g. suppressive activity and Treg proliferation, this study will provide insights into the role of DR3 signaling in the immunologically complex operation area of Tregs. In sum, an in-depth understanding of the TL1A/DR3 system will potentially also pave the way for further therapeutic exploitation and might offer new treatment strategies, e.g. for autoimmune processes.

• DFG Programme: Research Grants