Deciphering the function of CREB in regulatory T cells - regulator for type one versus type two immune-responses?

• Applicant: Professor Dr. Klaus Tenbrock
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 403181615

Regulatory T (Treg) cells are one of the most important players to prevent autoimmune disease and maintain immune homeostasis. The underlying mechanisms, which promote differentiation of Treg cells, are of utmost therapeutic importance and therefore a matter of intensive research. Previous studies describe that the transcriptional activator CREB induces generation and promotes maintenance of Treg cells by direct transcriptional mechanisms. In contrast to the current paradigm, we found that in vivo- depletion of CREB in Foxp3 positive cells enhances Treg cell frequencies and function. This furthermore involved induction of CREM expression, a transcription factor, which is associated with systemic lupus erythematosus (SLE) and shares the same binding site with CREB. In particular, Foxp3 specific deletion of CREB induced IL-10 as well as IL-13 and ST-2 in Tregs, which prevented the occurrence of inflammation in a model of experimental transfer colitis, while it induced spontaneous occurrence of activated B cells with elevated IgE levels. We thus hypothesize that CREB depicts unknown mechanisms of Foxp3 regulation and will unravel the role of CREB for expression and function of Tregs in 3 specific aims: 1. How does CREB regulate expression and function of Tregs?2. Is the interaction of CREM and CREB critical for Treg cell number and function?3. How is the expression of CREB regulated in human Tregs and does this have transcriptional and functional consequences?In detail we will investigate which CRE motifs are occupied by CREB and whether DNA methylation is affected in regulatory T cells in steady state and in inflammation using a model of experimental transfer colitis, we will delineate whether CREB deficient Tregs are Th2 prone using an OVA-induced Asthma model, whether the interaction of CREM and CREB is critical for the IL-10 regulation in Tregs using the CRE-lox system and whether the higher functionality of Tregs in CREB deficient mice is dependent on IL-10. Finally we will investigate Tregs of SLE patients, of patients with allergic asthma and of patients with inflammatory bowel disease as well as controls with regard to CREB/pCREB expression and subsequent functional consequences. A deeper understanding of these mechanisms might help to elucidate the reasons for the breakdown of T cell tolerance in autoimmune diseases but might also provide new treatment strategies to enhance function and/or numbers of Treg cells in autoimmune diseases.

• DFG Programme: Research Grants