Human T cell response to substrate rigidity for design of improved expansion platform
Cells have long been known to sense and respond to mechanical stimuli in their environment. In the adoptive immune system particularly, cells are highly specialized and responsible for detecting and eliminating pathogens from the body. T cell mechanosensing is a relatively new field that explores how force transmission in cell-cell interaction elicits both inter- and intra-cell signaling. Owing to recent advances in genetic manipulation of T cells, it has emerged as new tool in immunotherapy.
... in immunotherapy. We recently demonstrated human T cell activation in response to mechanical rigidity of surfaces presenting activating antibodies CD3 and CD28. The work in this dissertation highlights new progress in the basic science of T cell mechanosensing, and the utilization of this knowledge toward the development of a more specialized expansion platform for adoptive immunotherapies. Human T cells are known to trigger more readily on softer PDMS substrates, where Young's Modulus is less than 100 kPa as compared to surfaces of 2 MPa. While the range of effective rigidities has been established, it is important to explore local differences in substrates that may also contribute to these findings. We have isolated the rigidity-dependence of cell-cell interactions apart from material properties to optimize design for a clinical cell expansion platform. Though PDMS is a well understood biomaterial and has found extensive use in cellular engineering, a PA gel substrate model allows for rigidity to be tuned more closely across this specific range of rigidities and provides control over ligand density and orientation. These rigidity-based trends will be instrumental in adapting models of mechanobiology to describe T cell activation via the immune synapse. In what is generally accepted as the clinical gold-standard for T cell expansion, rigid (GPa) antibody-coated polystyrene beads provide an increase in the ratio of stimulating surface area-per-volume, over standard culture dishes. Herein we describe the development of a soft-mater [...]