Investigating the role of WNK1 in T cell killing

Cytotoxic CD8 T Lymphocytes (CTL) are a critical component of the adaptive immune system and are responsible for clearing virus infected cells and cancer cells by secreting a deadly cocktail of cytolytic enzymes through a specialized structure called the cytolytic synapse. This project aims to study the biochemical pathways that underly T cell killing.

Particularly, we are interested in the serine/threonine kinase WNK1, which until recently was mostly known for its role in regulating ion homeostasis in the kidney, but from which we now know is also a novel positive regulator of T cell killing.

Previous data by our lab has shown that in CTLs WNK1 is a negative regulator of integrin-dependent adhesion and a positive regulator of migration in response to chemokines.

New data obtained from CTLs doubly deficient for the well-studied WNK1 effectors OXSR1 and STK39, shows, that these, despite having the same adhesion and migration defects kill normally, suggesting that the killing defect is not due to those WNK1 function.

We therefore hypothesize that WNK1 directly controls the formation of the immune synapse by phosphorylating novel yet to be determined substrates.

We will therefore use a two-pronged approach and use high resolution imaging modalities to determine which step in the killing cascade is defective in combination with phospho-proteomics and biochemistry experiments to elucidate the underlying signalling pathways.