When T cells enter the tumor battlefield, they sense nearby antigens to inform their attacks. But chemical signaling isn’t the only property that shapes T cell function. In a recent paper, researchers described generating different T cell populations by altering mechanical properties of the cell environments.1 Their in vitro platform could improve production and customization of CAR T cell therapies. 

     Schematic showing blue cells moving through either an orange matrix to make orange cells or a purple matrix with black lines to make make purple cells.
Researchers tuned extracellular matrix viscoelasticity by adding crosslinkers to collagen-based hydrogels. By varying the degree of viscoelasticity, the researchers produced T cells with different phenotypes.
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“Different cell types just kill differently,” said Kwasi Adu-Berchie, a biomedical engineer at the Wyss Institute and coauthor of the paper. “We present other tools to generate some of these cell types.” 

In vitro systems are valuable tools for studying and manipulating immune cell function, but many platforms only focus on chemical signaling. “We are adding a whole new layer of sensing and signaling based on the mechanical environment that further refines the signals that are presented by antigen presenting cells,” said Manish Butte, an immunologist at the University of California, Los Angeles, who was not involved in the study.

To study mechanical forces on T cells, Adu-Berchie’s team generated 3D hydrogels that mimic the tumor tissue environment. By modulating the density of collagen, they controlled the gel’s stiffness. The team also introduced crosslinkers into closely linked collagen fibers to independently tune viscoelasticity, which is the time-dependent recovery after deformation.3 For example, both a rubber band and silly putty are elastic, but the speed it takes for each item to bounce back after stretching differs.

When the researchers cultured T cells in these different hydrogels, they found that viscoelasticity strongly influenced T cell phenotypes. More elastic, less viscous gels produced effector-like T cells, which quickly mount an attack, while a less elastic, more viscous environment produced memory-like T cells, which contribute to long-term immunity. The researchers found increased activation of the transcription factor activator-protein-1 in the effector-like cells. They observed similar elevations in T cells extracted from patient tumors, which bear comparable viscoelastic properties. 

The researchers hope to use these biomaterials to explore how mechanical cues shape other immune cells, such as natural killer cells and regulatory T cells. 

References

  1. Adu-Berchie K, et al. Nat Biomed Eng. 2023. 
  2. Du H, et al. Nat Rev Immunol. 2023;23:174-188.
  3. Chaudhuri O, et al. Nature. 2020;584:535-546.