T cell activation and immune synapse organization respond to the microscale mechanics of structured surfaces

Abstract

Cells have the remarkable ability to sense the mechanical stiffness of their surroundings. This has been studied extensively in the context of cells interacting with planar surfaces, a conceptually elegant model that also has application in biomaterial design. However, physiological interfaces are spatially complex, exhibiting topographical features that are described over multiple scales. This report explores mechanosensing of microstructured elastomer surfaces by CD4+ T cells, key mediators of the adaptive immune response. We show that T cells form complex interactions with elastomer micropillar arrays, extending processes into spaces between structures and forming local areas of contraction and expansion dictated by the layout of microtubules within this interface. Conversely, cytoskeletal reorganization and intracellular signaling are sensitive to the pillar dimensions and flexibility. Unexpectedly, these measures show different responses to substrate rigidity, suggesting competing processes in overall T cell mechanosensing. The results of this study demonstrate that T cells sense the local rigidity of their environment, leading to strategies for biomaterial design.

The CAR T‐Cell Mechanoimmunology at a Glance

“…[ 7–9 ] As seen in the conventional T‐cell study, cytotoxic T‐cell expressing TCRs can recognize and bind specific antigen molecules of peptide‐bound major histocompatibility complex (pMHC) expressed on the target cancer cell. During the process, T‐cell is highly mechanosensitive and the TCR activation and force generation are regulated by the local mechanical cues [ 10,11 ] and geometric arrangement of binding ligands. [ 12 ] Moreover, the force dynamically changes in the IS with a conformational transformation in the TCR–pMHC complex to guide the proper immune responses, [ 13,14 ] including rapid antigen sampling and serial secretion of lytic granules to the cancerous cells.…”

Modulating T Cell Activation Using Depth Sensing Topographic Cues

“…Previous microfabrication‐based studies of synaptic T cell protrusions convolved mechanosensing with morphosensing. [ 12,26 ] Here, we cleanly demonstrate that T cells are sensitive to topography alone, and that the sensing of that topography affects downstream transcriptional responses.…”

Unraveling the mechanobiology of immune cells

“…Microtubule organization at the cell-array interface shows the local contraction and expansion of CD4 + T cells. Varying pillar height and shape induces changes in T cell cytoskeletal organization and interferon- γ secretion, which is associated with the effector functions [ 42 • ]. Artificial antigen presenting surfaces consisting of patterned micro-dot arrays surrounded by a fluid supported lipid bilayer are also useful tools for mimicking pMHC nanoclusters.…”