# Integrin-Mediated Mechanosensing of Modeled Lymph Node Microenvironment Promotes T Cell Activation via Nuclear Deformation

## TL;DR

This study shows how mechanical stiffness in lymph nodes affects T cell activation through nuclear deformation, offering insights for better immunotherapy.

## Contribution

A novel T cell culture platform with tunable stiffness and decoupled interactions was developed to study mechanosensing in lymph nodes.

## Key findings

- T cells sense mechanical changes via RGD/integrin ligation in the microenvironment.
- Stiff matrices increase F-actin aggregation, leading to nuclear deformation and interleukin-2 expression.
- The platform provides a better in vitro model for studying T cell activation and expansion.

## Abstract

Upon tumor metastasis, lymph nodes (LNs) undergo mechanical stiffening, yet how this change influences T cell activation within the microenvironment remains incompletely understood. In particular, the dynamic mechanical forces during activation are transduced by cell–extracellular matrix (ECM) interactions, while cell–cell interactions persist. Here, we established a novel T cell culture platform using hydrogels with tunable stiffness and decoupled presentation of RGD peptide and anti-CD3 monoclonal antibody, separately mimicking ECM–T cell and T cell–antigen-presenting cell interactions. This platform closely mimics the LN microenvironment during T cell activation. By integrating experiments with mathematical modeling, we revealed that T cells sensed mechanical changes in the microenvironment requiring RGD/integrin ligation, while stiff matrix up-regulated F-actin aggregation instead of myosin contraction, deforming the nucleus and promoting yes-associated protein nucleus translocation, resulting in interleukin-2 expression and T cell activation. Our findings shed light on the mechanobiological mechanism underlying the potential benefits of immunotherapy in patients with LN metastases and provide an optimized mechanical platform for studying T cell activation and expansion in vitro.