The molecular Treg group studies molecular and genetic mechanisms involved in healthy and dysfunctional T cell biology. The immune system is a complex network with interaction of multiple cell types and tissues. Critically, understanding those interactions and the molecular and genetic events that determine consequences thereof requires most physiological in vivo systems. Where required, we therefore develop new genetic tools (inducible, reversible, conditional etc.) that do not require compromise on the objective of using physiological in vivo contexts.
This is especially true for regulatory T cells (Treg). Unlike other T cells, Treg are not pro-inflammatory and not equipped to fight infections. Treg are anti-inflammatory, indispensable in prevention of autoimmunity or other unwanted/uncontrolled immune responses.
Our lab follows two lines of research on T cell/Treg biology:
Mechanisms that underlie Treg plasticity
Treg plasticity is especially important to understand as a therapeutic target in both autoimmunity/inflammation (where plasticity can be detrimental) and cancer (where plasticity would be a boon). To understand how Treg stability is maintained and how Treg plasticity is driven we combine established experimental designs, new in vivo genetic toolsbased on latest CrispR/Cas advances and single cell proteomics and transcriptomics. This allows us to study (i) which Treg are poised to be unstable, (ii) which genes/pathways are involved in Treg stability and which ones promote Treg plasticity, (iii) which genes/pathways are critically involved in Treg fate memory and also, (iv) what happens to Treg that have lost Treg fate memory. Considering that maintaining Treg stability (e.g. during autoinflammation) as well as inducing Treg plasticity (in cancer) are attractive therapeutic targets, these questions are of fundamental interest.
Left: tSNE clustering of Treg and exTreg at different time points.
Right: Network-based analysis to dissect stable from unstable Treg.
RNA modifications in T cell biology
Previously in higher organisms in general and in the immune system in particular underappreciated regulatory mechanisms are RNA modifications. A multitude of those changes to RNA exist with different consequences for transcript stability, translation or open reading frame length; consequences directly impacting cellular development, homeostasis and function. Our lab focuses on the isomerization of uridine to pseudouridine, a process catalyzed by 13 non-redundant synthases. An accumulating number of case reports demonstrate causative mutations in pseudouridine synthases in neurological and metabolic disorders, highlighting the importance of this regulatory mechanism. In our group, we study the role of pseudouridylation in T cell and in particular Treg biology and function utilizing novel in vivo genetic tools as well as the combined power of CrispR/Cas and single-cell multi-omics in CROPseq. We aim to dissect the function of all 13 synthases in T cell homeostasis at steady state as well as in T cell function during disease.
In vivo CROPseq workflow
- KU Leuven (Belgium)
- FWO (Fonds Wetenschappelijk Onderzoek)