Single-cell topographical profiling of the immune synapse reveals a biomechanical signature of cytotoxicity

• DOI: 10.1126/sciimmunol.adj2898
• Publication Date: 2024-06-28T17:59:49Z
• Authors: Miguel de Jesus; Alexander H. Settle; Daan Vorselen; Thomas K. Gaetjens; Michael Galiano; Yevgeniy Romin; Esther Lee; Yung Yu Wong; Tian-Ming Fu; Endi Santosa; Benjamin Y. Winer; Fella Tamzalit; Mitchell S. Wang; Anthony Santella; Zhirong Bao; Joseph C. Sun; Pavak Shah; Julie A. Theriot; Steven M. Abel; Morgan Huse
• Keywords: Cytotoxicity, Immunologic; Mice, Inbred C57BL; 0301 basic medicine; Mice; 03 medical and health sciences; Immunological Synapses; Macrophages; Life Science; Animals; Single-Cell Analysis; T-Lymphocytes, Cytotoxic; Biomechanical Phenomena

Immune cells have intensely physical lifestyles characterized by structural plasticity and force exertion. To investigate whether specific immune functions require stereotyped mechanical outputs, we used super-resolution traction force microscopy to compare the immune synapses formed by cytotoxic T cells with contacts formed by other T cell subsets and by macrophages. T cell synapses were globally compressive, which was fundamentally different from the pulling and pinching associated with macrophage phagocytosis. Spectral decomposition of force exertion patterns from each cell type linked cytotoxicity to compressive strength, local protrusiveness, and the induction of complex, asymmetric topography. These features were validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, live imaging of synaptic secretion, and in silico analysis of interfacial distortion. Synapse architecture and force exertion were sensitive to target stiffness and size, suggesting that the mechanical potentiation of killing is biophysically adaptive. We conclude that cellular cytotoxicity and, by implication, other effector responses are supported by specialized patterns of efferent force.