Kurzfassung

Dendritic cells (DC), including Langerhans cells (LC) in the skin, are a heterogeneous family of professional antigen presenting cells (APC) that have the unique capacity to balance (auto-) immunity and self-tolerance. However, the molecular cues conferring a tolerogenic DC phenotype remain elusive. TGF-β is a pleiotropic immunosuppressive cytokine and we have recently discovered that
disruption of TGF-β signaling in DC is sufficient to break self-tolerance. Moreover, Wnt/β-catenin signals in...Dendritic cells (DC), including Langerhans cells (LC) in the skin, are a heterogeneous family of professional antigen presenting cells (APC) that have the unique capacity to balance (auto-) immunity and self-tolerance. However, the molecular cues conferring a tolerogenic DC phenotype remain elusive. TGF-β is a pleiotropic immunosuppressive cytokine and we have recently discovered that
disruption of TGF-β signaling in DC is sufficient to break self-tolerance. Moreover, Wnt/β-catenin signals in DC are required to maintain immune homeostasis in the intestine. These findings strongly suggest that enhanced TGF-β and β-catenin signaling promote a regulatory DC function.
In multiple sclerosis (MS) activation of myelin-reactive T cells leads to a chronic inflammatory disease of the human central nervous system (CNS), resulting in perivascular lesions, demyelination and axonal damage. Despite an incomplete understanding of how DC are involved in MS pathology, there is accumulating evidence from experimental autoimmune encephalomyelitis (EAE), the animal
model for MS, that DC contribute to perpetuation, and presumably also initiation of disease. Consequently, approaches to harness the regulatory function of DC with the ultimate goal to re-establish self-tolerance are attractive therapeutic strategies to treat MS. However, one of the hurdles so far in using tolerogenic DC as therapeutic tools is that the inflammatory environment of the affected CNS might augment their immunogenic function. As a result, the DC could exacerbate
the autoimmune reaction instead of inhibiting CNS disease.
We hypothesize that TGF-β and β-catenin signaling are crucial factors to induce a regulatory DC function in vivo, and that activation of these pathways in DC enables a safe DC-based treatment of chronic destructive CNS inflammation. To this aim, we have generated novel, unique mouse models,
in which these signaling pathways are either disrupted or constitutively active selectively in DC. In this research proposal we will (1) dissect the role of TGF-β and β-catenin signals to govern DC homeostasis and function; (2) identify how TGF-β and β-catenin control of DC function affects EAE; (3) establish the therapeutic potential of DC with enhanced TGF-β and β-catenin signaling to ameliorate EAE; and (4) determine the capacity of LC with constitutive TGF-β and β-catenin signaling to improve EAE. We expect that our work will reveal that TGF-β and β-catenin signals indeed instigate a robust tolerogenic DC phenotype in vivo that will remain stable during ongoing autoimmune CNS inflammation. This project combines our extensive expertise in DC biology with a strong neuroimmunology research team, which will be critical for successful completion of the proposed experiments.» weiterlesen» einklappen