Elastic Microstructures: Combining Biochemical, Mechanical, and Topographical Cues for the Effective Activation and Proliferation of Cytotoxic T Cells

The ex vivo activation and proliferation of cytotoxic T cells are critical steps in adoptive immunotherapy. Today, T cells are activated by stimulation with antibody-coated magnetic beads, traditionally used for cell separation. Yet, efficient and controlled activation and proliferation of T cells require new antibody-bearing materials, which, in particular, deliver mechanical and topographic cues sensed by T cells. Here, we demonstrate a new approach for the activation and proliferation of human cytotoxic T cells using an elastic microbrush coated with activating and costimulatory antibodies. We found that the microbrush topography affects the protrusion of the cell membrane and the elastic response to the forces applied by cells and can be optimized to yield the strongest activation of T cells. In particular, T cells stimulated by a microbrush showed a three-fold increase in degranulation and release of cytokines over T cells stimulated with state-of-the-art magnetic beads. Furthermore, the microbrush induced a T-cell proliferation of T cells that was more prolonged and yielded much higher cell doubling than that done by the state-of-the-art methods. Our study provides an essential insight into the physical mechanism of T-cell activation and proliferation and opens the floodgates for the design of novel stimulatory materials for T-cell-based immunotherapy.