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Regulation of cytotoxic T lymphocyte activity at the lytic synapse

Final Activity Report Summary - CYTOLYTIC SYNAPSE (Regulation of cytotoxic T lymphocyte activity at the lytic synapse)

The EXT project CYTOLYTIC SYNAPSE focused mainly on the study of cytolytic T lymphocytes (CTL), as central players of our immune system. Upon recognition of a specific antigen, CTL can directly kill virus-infected cells and tumour cells by delivering lytic granules at the immunological synapse (IS), a structure corresponding to a 'cellular kiss'. Our main objective was to better define how the remodelling of actin (thin filaments making up the cytoskeleton) regulates the interaction between CTL and target cells at the IS. For that purpose, we studied CTL from Wiskott-Aldrich syndrome (WAS) patients as 'natural models'. Indeed, WAS is a life-threatening primary immunodeficiency caused by mutations in the gene encoding WASP, a key actin regulator in immune cells.

Each researcher within the Team (1 early-stage researcher and 3 experienced researchers) was in charge of a specific project. The main scientific achievements obtained are the following: WASP regulates the molecular organisation and the stability of the IS; WASP regulates CTL cytotoxic activity, in particular against tumoural B cells ; tumoural B cells activate an abnormal actin remodelling program to regulate their motility. In addition, we provide a novel analytical method to study lytic granule composition and contribute to the preclinical validation of gene therapy for WAS.

This project illustrates how the study of a rare disease as a model can yield data that are relevant way beyond the specific disease studied. Indeed, the study of a WAS patient with a secondary mutation was instructive in that it represents a case of 'natural gene therapy'. Our expertise on molecular regulation of actin cytoskeleton remodelling in lymphocytes from WAS patients was used to investigate how malignant lymphocytes remodel their actin cytoskeleton as a 'strategy' to migrate and invade tissues.