Corrado, Mauro - B 03

T cells dynamically expand and contract following antigen-specific stimuli and microenvironmental cues. As a result, immunological memory protects us from following antigen-specific attacks. Alterations of the mechanisms regulating this process are responsible for autoimmunity or impaired immune protection. Mitochondrial fitness centrally regulates memory T cell differentiation and function. It provides metabolic reserve capacity to allow long lasting survival of memory T cells. It also controls critical steps in epigenetic remodeling, chromatin accessibility and transcriptional profile of T cells by producing and buffering Acetyl-CoA and other metabolites. By combining the analysis of gene expression and chromatin accessibility of effector and memory T cells, we identified previously uncharacterized common hits regulated during memory T cell differentiation. Of note, these hits share a signature for some specific transcription factors, whose role in the immune system has never been studied. We hypothesize that these transcription factors might integrate metabolic and epigenetic signals to establish persistent immunological memory. By complementing metabolic and immunologic phenotyping with cutting edge sequencing approaches, the project will reveal novel insights into the epigenetic and metabolic network necessary to establish long-term immune memory and surveillance against cancer and recurrent infections.

Hotspot mutations in the tumour suppressor p53 are the most common mutations in human cancers. Suppression of the apoptotic defect in cells carrying mutated p53 is of major therapeutic interest because it might be applicable to a large number of tumour entities. Here, we will identify bypass mechanisms that could offer new therapeutic routes for specifically reinstating the apoptotic response in cancer cells carrying hotspot mutations in p53. Our project has thus a major translational and potentially therapeutic perspective.

• Integrate epigenetic and transcriptional profiles of T_EFF and T_MEM cells
• Identify and validate the role of transcription factors regulated during memory T cell differentiation via pharmacological inhibition and genetic deletion in primary T cells
• Generate a T cell specific KO mouse model of the most promising validated transcription factor
• Study the immune response to infection and the in vivo mechanism of T_MEM cells generation in the KO mouse model