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NEW YORK (Reuters Health) – Researchers have discovered that leukocytes become up to 10 times stiffer and more viscous during activation, as the cells prepare to engage their targets.
“Leukocytes generate forces when they activate in contact with another cell,” Dr. Julien Husson of Institut Polytechnique de Paris in Palaiseau told Reuters Health by email. “Our study now shows that in addition to generating forces, leukocytes undergo large mechanical changes: they become stiffer and more viscous. What is yet to understand is how necessary these mechanical changes are for force generation, and overall, for the proper activation of leukocytes.”
“One can speculate that manipulating these mechanical changes could be a new way to favor a better activation of leukocytes,” he suggested. “This could have future applications in the context of cancer and the elimination of cancer cells by T cells. Indeed, cytotoxic T cells can be present in tumors but inhibited by the tumor microenvironment, so that they do not attack the tumor.”
“Manipulating the cytoskeleton on T cells, which is mainly responsible for cell mechanical changes, could favor the ‘awakening’ of killer T cells so that they start attacking their surrounding tumor cells,” he said. “‘Waking up’ these killer cells is the goal of some recent cancer immunotherapies, which target specific T cell receptors in order to cut inhibitory signals sent by the tumor.”
As reported in the Biophysical Journal, using the team’s novel micropipette-based rheometer to track cells’ viscosity and elasticity, the team studied three different types of leukocytes. They showed that leukocytes become up to 10 times stiffer and more viscous during activation, and that the elastic and viscous properties evolve in parallel, preserving a ratio characteristic of the leukocyte subtype.
Specifically, they used a bead coated with antibodies to apply an oscillating force to the leukocyte, causing the cell to activate and latch onto the bead. The cell’s stiffness was calculated from the the tiny protrusion induced by the oscillation, and viscosity was calculated from the delay between an oscillation and the resulting protrusion.
Their work provides a new way to investigate the mechanical properties of cells, the authors note, and also suggests that these measurements can help discriminate among leukocyte subtypes during activation.
They conclude, “These mechanical measurements set up a complete picture of the mechanics of leukocyte activation and provide a signature of cell function.”
Immunologist Dr. Anil Bamezai of Villanova University, whose expertise is in T-lymphocyte signaling/activation and membrane biology, commented in an email to Reuters Health, “The authors have provided compelling evidence concerning activation-induced changes in the leukocyte membrane viscosity and elasticity.”
“The most interesting and surprising data…is the rapid nature of the change in viscoelasticity,” he said. “The observed mechanical change is faster than previously reported biochemical changes associated with leukocyte cell signaling.”
“Understanding the contribution of the mechanical changes in the membrane to the overall cell signaling/activation,” he said, “will help us develop a comprehensive understanding of signaling pathways/networks during activation of leukocytes. Assessing stiffness in membranes of disease patient’s leukocytes and comparing it with healthy individuals will help assess its clinical potential.”
Dr. Manish Butte, Division Chief of Immunology, Allergy, and Rheumatology at the University of California, Los Angeles, also commented by email. “This new finding fits into a larger body of work, all quite recent, that has sought to understand the mysteries around why tissues swell and rigidify during infections or inflammation.”
His own lab showed that “immune cells change their metabolic activity as they sense the mechanical stiffness of tissue they’re crawling through,” he told Reuters Health. “Combining these two ideas, the clinical implication is that the degree of tissue inflammation sends cues to the immune cells so they can calibrate how much vigor is needed to respond — stiffer, more infected tissues might imply bigger infections and beget stronger immune responses.”
“The clinical impact of this work is yet to be realized,” he said, “but multiple groups are starting to translate these basic findings into methods to amplify immune responses during infections.”
SOURCE: https://bit.ly/3sjuQpg Biophysical Journal, online March 21, 2021.
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