The role of T cell SMAD7 in cellular immunity and in the regulation of autoimmune inflammation in the central nervous system

• Applicant: Dr. Ingo Kleiter
• Subject Area: Immunology
• Term: from 2007 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 34814745

The cytokine TGF-β is a master regulator of T cell function. We hypothesized that downregulation of Smad7, the intracellular inhibitor of TGF-β, would dampen autoimmune inflammation. Previously, we have shown that mice with a T cell-specific Smad7-deletion have reduced disease and CNS inflammation in an animal model of multiple sclerosis. Interestingly, disease susceptibility correlated with Th1 but not Th17 responses. Now, we intend to examine how TGF-β and Smad7 regulate T cell differentiation and effector function on a cellular and molecular level and which consequences this has for experimental infection models. Therefore, we want to analyse whether TGF-β signals in T cells are exclusively transmitted through the Smad pathway or by alternative pathways and if Smad7 has functions independent from its ability to block TGF-β signalling. Furthermore, we want to characterize how the interaction of T cells and antigen presenting cells is modulated by aberrant TGF-β signalling. Finally, we want to examine how a Smad7-deletion changes susceptibility to infection with bacteria and fungi. In summary, the objective of this project is to better understand the regulation and function of Smad7 in T cells, which will facilitate the development of specific immune-based therapeutics aiming to dampen inflammation.

• DFG Programme: Research Units
• Subproject of: FOR 876: Mechanisms Dampening Inflammation
• Participating Person: Privatdozent Dr. Andreas Steinbrecher