Biomaterials Approach Explores Tissue Mechanics' Impact on T Cell Development and Function

Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard John A. Paulson School of Engineering and Applied Sciences took a novel biomaterials approach to investigate how tissue mechanics influence the characteristics and functions of T cells, with the goal of improving the efficacy of adoptive T cell therapies.

By engineering a 3-dimensional model of the extracellular matrix (ECM), which determines tissue stiffness and viscoelasticity, the research team was able to independently manipulate these parameters. This allowed them to demonstrate the distinct impact of tissue viscoelasticity on T cell development and function both in vitro and in vivo. The study, published in Nature Biomedical Engineering, also identified a molecular pathway underlying this phenomenon.

Tissue mechanics are defined by their stiffness and viscoelasticity, representing the resistance to instantaneous deformation and the relaxation behavior over time, respectively. The team engineered hydrogels using collagen, a major protein in the ECM, to mimic the mechanical properties of different tissues. By varying the concentration of collagen molecules and the cross-linking density, they could tune the stiffness and viscoelasticity of the hydrogels. These ECM-mimicking hydrogels allowed the attachment and stimulation of T cells with specific mechanical signals.

The study revealed that T cells exposed to more elastic collagen matrices tended to develop into effector-like T cells, while those in more viscous matrices became memory-like T cells. Furthermore, the T cell's state influenced by the viscoelasticity of the matrix was long-term imprinted, even when transferred to a different matrix, suggesting implications for future cell manufacturing. Gene expression analysis pointed to the involvement of a transcription factor called AP-1, which linked T cells' response to mechanical environments with specific gene expression programs.

The findings were validated using therapeutic CAR-T cells, demonstrating that T cells stimulated in more elastic collagen matrices exhibited enhanced cytotoxicity against lymphoma cells. In animal models, CAR-T cells stimulated in more elastic matrices effectively reduced tumor burden and prolonged the survival of mice.