Effect of the Environmental Mechanical Heterogeneity on T Cell Function

Abstract

T cells, key players in the immune system, recognize antigens via T-cell receptors (TCRs) and require additional costimulatory and cytokine signals for full activation. Beyond biochemical signals, T cells also respond to mechanical cues such as tissue stiffness. Traditional ex-vivo mechanostimulating platforms, however, present a uniform mechanical environment, unlike the heterogeneous conditions T cells encounter in-vivo. This work introduces a novel mechanically heterogeneous environment, with alternating soft and stiff microdomains, to mimic the complex mechanical signals T cells face. Results show that T cells exposed to this heterogeneous environment do not average the mechanical signals but instead respond similarly to those on a homogeneously soft surface, leading to lower activation compared to those on a stiff surface. Interestingly, long-term exposure to these patterns enhances the proliferation of central memory and effector T cell phenotypes, similar to stiff environments. These findings reveal the non-linear nature of T cell mechanosensing and suggest that mechanical heterogeneity plays a critical role in modulating T cell responses, providing new insights into T cell activation and potential implications for immunotherapies.