Augmentation of T-Cell Activation by Oscillatory Forces and Engineered Antigen-Presenting Cells

Abstract

Activation of T cells by antigen presenting cells (APCs) initiates their proliferation, cytokine production, and killing of infected or cancerous cells. We and others have shown that T-cell receptors require mechanical forces for triggering, and these forces arise during the interaction of T cells with APCs. Efficient activation of T cells in vitro is necessary for clinical applications. In this paper, we studied the impact of combining mechanical, oscillatory movements provided by an orbital shaker with soft, biocompatible, artificial APCs (aAPCs) of various sizes and amounts of antigen. We showed that these aAPCs allow for testing the strength of signal delivered to T cells, and enabled us to confirm that that absolute amounts of antigen engaged by the T cell are more important for activation than the density of antigen. We also found that when our aAPCs interact with T cells in the context of an oscillatory mechanoenvironment, they roughly double antigenic signal strength, compared to conventional, static culture. Combining these effects, our aAPCs significantly outperformed the commonly used Dynabeads. We finally demonstrated that tuning the signal strength down to a submaximal “sweet spot” allows for robust expansion of induced regulatory T cells. In conclusion, augmenting engineered aAPCs with mechanical forces offers a novel approach for tuning of T-cell activation and differentiation.

Unraveling the mechanobiology of immune cells

“…Mechanistically, on stiffer substrates, YAP mediates enhanced translocation of nuclear factor of activated T cells (NFAT) into the nucleus, resulting in increased T cell activation and effector function [ 40 ]. Interestingly, simply applying mechanical forces via oscillation on a shaker leads to greater T cell expansion and activation, compared to static conditions [ 41 ], which may due to more effective encountering and contact between T cells and engineered APCs at the optimal oscillation frequency.…”

“… [ 55 ] T lymphocyte Compared to static culture, an oscillatory mechanoenvironment doubles antigenic signal strength for CD8 + T cell expansion. [ 41 ] Squeezing T lymphocyte Squeezing cells through a microfluidic device mechanically disrupts cell membrane for drug delivery and results in minimal aberrant transcriptional responses. [ 54 ] Microstructure confinement Macrophage Spatial confinement downsizes the inflammatory response of macrophages.…”

“…Unlike electroporation, which disrupts the expression profile of human T cells, squeezing results in minimal aberrant transcriptional responses [ 54 ]. Moreover, an oscillatory mechanoenvironment shows better antigenic signal strength, compared to conventional, static culture for CD8 + T cell expansion [ 41 ]. Thus, novel engineering tools and materials can be developed and tailored to control immune cell functions.…”

Nano-in-Micro Dual Delivery Platform for Chronic Wound Healing Applications

“…Here, we utilized microfluidic technology to control the formation of polysaccharide microparticles. Microfluidic platforms have recently attracted great attention due to their possibility of better controlling physical properties of formed particles including their size, shape, and dispersity [26][27][28][29][30][31]. In the current study, a microfluidic droplet generator was used ( Figure 1A).…”

Artificial Engineering of Immune Cells for Improved Immunotherapy

“…Reproduced with permission. [ 88 ] Copyright 2019, ACS Publications. e) Schematic showing the tumor cell‐T cell recognition mediated by the bispecific aptamer (cb‐aptamer) for targeted T cell‐based immunotherapy.…”