Abstract: Mechanical force is an emerging determinant of the cellular immune response. Recent evidence indicates that immune cells regulate their cell mechanics to dynamically adapt to their surroundings. Quantifying mechanical force has therefore become a contentious challenge across multiple disciplines at the interface of biophysics and immunology. Mechanical force is especially important for the activation of T cells. Applying sensitive quantitative super-resolution imaging and force probing methodologies to analyse resting and activated T cells, we demonstrate that the kinetics of the antigen engaging the T-cell receptor controls the nanoscale actin organisation and mechanics of the immunological synapse. Using an engineered T-cell system expressing a specific T-cell receptor and stimulated by a range of antigens, force measurements revealed that the peak force experienced by the T- cell receptor during activation was independent of the kinetics of the stimulating antigen. Conversely, quantification of the actin retrograde flow velocity at the immunological synapse revealed a striking dependence on the antigen kinetics. Consequently, tuning actin dynamics in response to antigen kinetics may thus be a mechanism that allows T cells to adjust the length- and time-scale of T-cell receptor signalling. Harvesting these insights into mechanobiology of T cells, we engineer synthetic antigen presenting cells to control T-cell differentiation. Novel ultra-thin superextended lightsheet technology allow to sensitive imaging of T-cell activation across scales. Taken together, the Biophysical Immunology Laboratory now democratises some of these established technologies with the microscopy company ZEISS in the Oxford-ZEISS Centre of Excellence.

Biography: Marco Fritzsche is a Full Professor and Scientific Director of the Oxford-ZEISS Centre of Excellence. He leads the Biophysical Immunology Laboratory between the Rosalind Franklin Institute and the Kennedy Institute for Rheumatology at the University of Oxford, UK. The BPI Laboratory aims to unravel the impact of biophysics and mechanobiology on the human immune response in health and disease. For this mission, the BPI lab develop custom-built microscopy technology at the interface of biophysics and immunology. Professor Fritzsche holds a MSc in theoretical physics and conducted his PhD in experimental biophysics and cell-biology at the London Centre for Nanotechnology at the University College London, UK. He performed his Postdoctoral work at the University of Oxford in close collaboration with the Howard Hughes Medical Institute Janelia Farm, USA.