Regulatory Role of Microvilli Formation and Receptor Clustering in T Cell Signal Transduction

• Applicant: Professor Dr. Enrico Klotzsch
• Subject Area: Immunology ; Biomaterials ; Biophysics ; Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566581557

This project aims to investigate the role of microvilli formation and receptor clustering in regulating T cell activation, particularly in response to Epstein-Barr virus (EBV) infection. The focus is on how antigen recognition translates into intracellular signaling and immune response. The study will explore how T cell receptor (TCR) activation is influenced by mechanosensitive processes, membrane curvature, and nanoscale surface structures. TCR-pMHC interactions allow cytotoxic T cells (CTLs) to recognize and destroy infected cells, but binding affinity alone does not fully explain immune responses. Microvilli, small actin-rich structures on T cells, play a key role in antigen recognition and signal amplification by clustering TCRs. Preliminary data suggest that microvilli stabilize TCR clusters and enhance activation. Additionally, experiments with nanoporous surfaces indicate that T cells can be activated independently of pMHC engagement, possibly through the mechanosensitive ion channel Piezo1. The project will define the role of TCR clustering in microvilli formation, evaluate how pMHC affinity influences T cell activation, investigate mechanosensitive regulation of TCR signaling, and study dendritic cell-T cell interactions. The first aim is to identify how microvilli stabilize TCR clusters and enhance activation. The research will use high-resolution microscopy to map the spatial distribution of key signaling proteins. The second aim is to compare different EBV-derived pMHC complexes to determine their effects on microvilli formation and TCR clustering. The third aim is to explore how membrane curvature and tension influence Piezo1 ion channel activity in T cells, potentially leading to pMHC-independent activation. The fourth aim is to investigate how dendritic cells influence microvilli formation and signal transduction during antigen presentation. The study will employ advanced microscopy techniques, including single-molecule imaging, super-resolution microscopy, and lattice light sheet microscopy. Flow cytometry and cytokine assays will be used to measure T cell activation. Nanoporous substrates will be tested to analyze their impact on TCR clustering and signaling. The expected outcomes include a deeper understanding of antigen recognition in T cells, insights into the mechanical forces regulating immune responses, and potential applications for improving T cell-based immunotherapies. The findings could also contribute to new biomaterial-based strategies for immune cell activation. The research will contribute to fundamental immunology, mechanobiology, and potential medical applications in immunotherapy.

• DFG Programme: Research Grants