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T cell regulation in chronic inflammation

Friday 13 January 2017

T cell regulation in chronic inflammation
Dr. Femke van Wijk

Juvenile idiopathic arthritis (JIA) is one of the most common childhood chronic inflammatory diseases with serious disability and loss of quality of life. During local treatment, synovial fluid (SF) containing high numbers of immune cells is aspirated, providing a unique model to compare blood T cells with cells from the local inflammatory environment. Under healthy conditions regulatory T cells (Treg), control and down-regulate immune responses to prevent excessive tissue damage. There is still a fundamental gap however in our understanding of immune regulation and development in (autoimmune) inflammatory settings. One of our key findings has been that not intrinsic Treg defects, but instead, T effector cells that become resistant to suppression by Treg are the main reason for impaired T cell regulation at the site of inflammation and we are currently investigating the mechanisms of resistance induction. In addition we are investigating clonal expansion and “hyper-specialization” of Treg under inflammatory conditions (ccollaboration Dr. B. Vastert, Dr. J. van Loosdregt Dr. M. Mokry).

Specific projects include:
- Functional specialization and clonal expansion of Treg in inflammation
- Molecular pathways of Treg programming

Techniques: Human cell culture, Flow cytometry, RNA-seq, Chip-seq, Functional T cell/APC assays, TCR-sequencing, CyTOF,

Tissue T cells
Inflammation itself is mostly evident in specific target tissues such as the intestine in IBD. In recent years, the novel concept of tissue resident T cells that have undergone specific tissue-instructed differentiation has emerged. Because of their long-term persistence in tissue they are likely culprits for relapses of tissue inflammation. Additionally, derailment of local regulatory processes, involving (unique) tissue resident Treg, may also foster disease. We are only beginning to understand human tissue T cell functional specialization, and my lab has optimized T cell tissue/tissue exudate isolation techniques that allow access to these satellite control rooms of persistent inflammation and relapse. We have implemented 3D imaging techniques to study the interaction between tissue T cells and other cells and perform single cell deep profiling to study local T cell development. To define common pathways of differentiation and possible derailment we are currently comparing T cells from different tissues (amongst others gut, skin, muscle, uterus, joint) and from multiple inflammatory diseases (collaborations Dr. B Oldenburg, Dr. B van Rijn, Dr. A. van Royen, Dr. M. Mokry).

Specific projects include:

- T cell tissue residency induction and programming: the role of endothelial cells.
- T cells changing fate in the gut
- Intestinal resident T cells as the culprit of local IBD relapses: how to target them?
- Role of T(reg) cells at the unique maternal-fetal interface

Techniques: Human cell culture, Flow cytometry, RNA-seq, single cell RNA-seq and TCR-seq, Functional T cell/APC assays, 3D imaging

Duration: 8 weeks-9 months

Contact: dr Femke van Wijk f.vanwijk@umcutrecht.nl