Background. Cytotoxic T cells, key components of the immune system, eliminate infected and cancerous cells through the so-called immunological synapse (IS), a highly organized structure formed between T cells and their target cells that facilitates antigen recognition, adhesion, and the release of cytokines and cytotoxic molecules. Architecturally, the IS is composed of multiple actin networks that play a critical role in IS formation and function.

To ensure proper assembly and turnover, these actin networks are regulated by actin-binding proteins and their associated regulatory factors. A key actin regulator of actin within the IS is WDR1, which, if mutated, leads to abnormal IS morphologies. In addition, mutations in the beta-actin encoding ACTB gene, have been associated with developmental defects and thrombocytopenia. Thus, although not directly linked to T cell dysfunction, these mutations may contribute to immunodeficiency. Despite this evidence, the precise role of actin as a structural and functional modulator of the IS remains elusive.

Project. Supported by a new ANR-DFG grant, PioneerCampus PI Marion Jasnin, together with her colleagues Loic Dupré (Institute for Infectious and Inflammatory Diseases, Toulouse) and Alphée Michelot (IBDM, Marseille), will address this knowledge gap and determine the precise architecture and function of actin networks within the IS.

Specifically, by studying primary T cells from healthy donors and patients with WDR1 or ACTB mutations, they will investigate a) the precise structure of the actin networks within the IS, b) how mutations in actin or actin regulatory proteins affect IS function, c) how these actin networks generate forces during IS formation and contribute to its function, and d) how actin homeostasis is maintained between the different actin networks within the IS.

Outlook. The findings from ACTIS could have profound implications for the development of novel therapies to improve T-cell function and treat immune-related diseases. By unlocking the secrets of the immunological synapse, the team is paving the way for more effective immune responses and improved patient outcomes in the future.