Open Research Projects

Epigenetic mechanisms in T cell senescence and aging

Prinicipal Investigator

Scientific interest within the context of the graduate college:

The three-dimensional structure of the genome – the epigenome – contributes significantly to the regulation of gene expression and forms the molecular basis for each cell type-specific transcription profile. In contrast to the DNA sequence, however, the epigenome can be modified by external influences and can therefore adapt the gene expression profile of a cell to new circumstances (e.g. in the case of differentiation, aging, environmental influences).

Our laboratory investigates the epigenetic regulatory mechanisms in immune cells, which have to react particularly flexibly to external influences (infection, inflammation, microbiota, aging, etc.). We profile genome-wide epigenetic structures to identify key elements that make a decisive contribution to the generation and function of immune cells during health1 and in situations of misguided immune reactions (e.g. chronic inflammation and autoimmunity). These elements will help to clarify the molecular reasons for misregulated immune reactions and might represent promising therapeutic targets. Furthermore, in situations where immune cells serve as therapeutic agents to regain health (advanced therapy medicinal products, ATMPs, such as adoptive cell therapy) epigenetic structures may be used as biomarkers for quality and safety control purposes2, and also as molecular switches for gene expression (‘epigenetic editing1,3), which may equip cell products with desired characteristics.

Project description:

The immune system, and especially T lymphocytes, go through aging processes that contribute to a reduced effectiveness of the immune system in old age (so-called: immune aging). Epigenetic mechanisms also contribute to immune aging. We were able to show that characteristic changes occur in the DNA methylation profile of T cells, which appear to be caused by proliferation-induced senescence processes.1,4 Interestingly, a large part of these changes occur in the transcriptionally silent part of the genome, the heterochromatin, in which genes are packaged for permanent repression. In this project, we want to generate genome-wide DNA methylation profiles of various T cell subsets specific for acute or chronic viruses in young and elderly people. Based on these molecular signatures, we want to clarify the DNA methylation changes, which are induced by proliferation-induced senescence during acute or chronic antigen exposure as well as during physiological aging of the human body. These results might also be of relevance for autoimmune and chronic inflammatory diseases as the activation and proliferation history of T cells accumulates in patients over time due to chronic or repetitive antigen encounter. Furthermore, this study will also reveal potential molecular targets for the rejuvenation of T cells, which might be useful for the application of T lymphocytes as ATMPs. This project requires the application of various methods from cell biology (e.g. flow cytometry, T cell isolation and culture), molecular biology (e.g. DNA methylation profiling) as well as bioinformatics (e.g. analysis of array-based genome-wide DNA methylation profiles), all of which are established in our lab and can be learned by the doctoral student.

Application details

References

  1. Durek P, Nordström K, Gasparoni G, […], Walter J, Hamann A, Polansky JK. Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development. Immunity. 2016; 45:1148-1161, doi: 10.1016/j.immuni.2016.10.022.
  2. Ou, K, Hamo D, Schulze A, […], Schmueck-Henneresse M, Reinke P, Polansky, JK.Strong Expansion of Human Regulatory T Cells for Adoptive Cell Therapy Results in Epigenetic Changes Which May Impact Their Survival and Function. Front Cell Dev Biol. 2021; 9:751590. doi: 10.3389/fcell.2021.751590.
  3. Kressler C, Gasparoni G, Nordström K, […], Walter J, Hamann A, Polansky JK. Targeted De-Methylation of the FOXP3-TSDR Is Sufficient to Induce Physiological FOXP3 Expression but Not a Functional Treg Phenotype. Front Immunol. 2020; 11:609891. doi: 10.3389/fimmu.2020.609891.
  4. Salhab A, Nordström K, Gasparoni G, […], Lengauer T, Manke T, DEEP Consortium, Walter J. A comprehensive analysis of 195 DNA methylomes reveals shared and cell-specific features of partially methylated domains. Genome Biol. 2018; 19:150, doi: 10.1186/s13059-018-1510-5.