Architecture of actin networks at the T cell synapse: impact of genetic variants in WDR1 and ACTB

• Applicant: Dr. Marion Jasnin
• Subject Area: Immunology ; Biophysics ; Structural Biology ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545495544

Cytotoxic T cells are an essential component of the adaptive immune system and pivotal not only for killing intracellular pathogens, but also for eliminating mutated and malignant cells. The property of cytotoxic T lymphocytes to eradicate infected or tumor cells relies on their ability to establish stable, direct contacts with their target cells and release cytotoxic molecules via a highly organized structure known as the immunological synapse (IS). Importantly, the actin cytoskeleton sustains the formation and function of the IS, particularly by regulating target cell adhesion and polarized delivery of cytotoxic molecules. The essential role of actin in this process is exemplified by the severity of rare genetic diseases, so-called immune-related actinopathies, that originate from deficiencies in actin regulatory proteins. Their clinical manifestation is characterized by a state of immunodeficiency, partly attributable to cytotoxic T lymphocyte dysfunction. Despite the knowledge gained from studying immune-related actinopathies, the precise organization of the different actin filament networks at the IS of primary T lymphocytes remains poorly defined, especially in patients. Yet, such a refined understanding will be essential not only to decipher the mechanisms underlying immune-related actinopathies, but also to characterize the fundamental mechanisms ruling T lymphocyte activation and function. ACTIS aims at exploring the IS-sustaining actin architecture from an ultrastructural, molecular and mechanical angle to provide a cross-scale understanding of how healthy cytotoxic T lymphocytes coordinate the adhesion and polarized delivery of cytotoxic molecules to their target cells. The knowledge acquired and the analytical tools developed herein will then be applied to the study of T lymphocytes from immuno-compromised patients carrying mutations in the actin-binding protein WDR1 to investigate its role in the organization of actin networks at the IS. ACTIS will also assess how natural variants in the beta-actin gene associated with syndromic developmental pathologies may impact T cell function as a possible underlying cause of susceptibility to infection in patients. In summary, ACTIS is set to identify fundamental mechanisms governing actin organization across scales that promote human T cell cytotoxicity. The insights gained will inspire novel therapeutic strategies, making ACTIS a pivotal endeavor in advancing our understanding of immune responses and the discovery of potential treatments.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partners: Dr. Loic Dupre; Dr. Alphée Michelot