Control of T cell tolerance and regulation through NFAT complex formation

• Applicant: Professor Dr. Vigo Heissmeyer
• Subject Area: Immunology
• Term: from 2007 to 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 46137870

The investigation of molecular mechanisms of immune tolerance should lead to the development of specific therapies for autoimmune diseases. T cells play a central role in the etiology of many autoimmune diseases. Signaling through the T cell receptor leads to activation of the transcription factor Nuclear Factor of Activated T cells (NFAT). The underlying hypothesis of this proposal is as follows: The decision whether a T cell commits to productive activation or, alternatively, enters a tolerance program is made by NFAT complex formation with different interaction partners. Accordingly, experimental manipulation of interaction partner availability is expected to change the transcriptional program and thereby the cellular phenotype. In order to test this hypothesis, we will manipulate different transcriptional programs and evaluate the impact on T cell responses. We will induce NFAT dependent, activation protein 1 (AP-1) independent transcription and determine whether this is sufficient to induce a state of adaptive tolerance in T cells. As a second focus, we will expand on our recent finding that Forkhead box P3 (Foxp3) can bind with NFAT on composite NFAT/AP-1 sites, forming a complex that is required for regulatory T cell (Treg) function. We will determine whether NFAT/Foxp3 complex formation is required for Treg development or functions during Treg-mediated bystander suppression. As a possible therapeutic avenue, we will determine whether co-expression of constitutively active NFAT together with Foxp3 can induce a stable regulatory T cell phenotype. Finally, we will address whether complex formation with AP-1 antagonizes NFAT function in adaptive tolerance and regulatory T cell activity.

• DFG Programme: Research Grants