In atomic-force microscopy image of a T-cell, dark purple indicates stiffer sections and lighter purple represents softer spots. Image: Courtesy of Dr. Manish Butte
When the T-cell recognizes an antigen, it gives the cell presenting the antigen a “hug,” so to speak, instead of a handshake. This initial interaction causes the T-cell to search nearby to find other cells that are presenting the same antigen to give them “hugs” as well. UCLA researchers have discovered that after the initial hug, T-cells become more gregarious, giving something more like a bear hug to any cell presenting its antigen.
These larger hugs help to activate the T-cell, equipping it to go out into the body and coordinate multi-cellular attacks to fight infections or cancers. The UCLA team learned that how stiff or soft T-cells are controls their response — the cells react slowly when they are stiff and trigger easily when they are soft. “T-cells are like the shy person at the office holiday party who acts stiff until they loosen up a bit and then are all over the dance floor,” says Manish Butte, MD, PhD, associate professor of pediatrics and microbiology, immunology and molecular genetics.
Dr. Butte and his colleagues pioneered an approach using an instrument called an atomic-force microscope to make real-time observations about what excites T-cells at the nanoscale. Once they learned that T-cells soften after activation, the UCLA team identified the biochemical pathway that controls the cell’s stiffness. Then they identified drugs that can help the T-cells either elicit or subdue a response. The finding provides scientists with a new capability to manipulate the immune system, Dr. Butte says.
Diseases arise in people and animals when T-cells attack the body’s other cells, or when they fail to signal attacks against cancer cells or infectious pathogens. “Until now, we had a limited understanding of what controls T-cell activation,” says Dr. Butte, chief of pediatric allergy and immunology at UCLA Mattel Children’s Hospital and a member of the UCLA Children’s Discovery and Innovation Institute. “Now that we understand the precise steps taking place, our findings suggest that altering T-cell stiffness with drugs could one day help us thwart diseases where T-cells are too active or not active enough.”
Dr. Butte and his colleagues are beginning to apply these findings to diminish the role T-cells play in triggering type 1 diabetes. “We can’t talk about precision medicine and still use a sledgehammer to treat disease,” Dr. Butte says. “By exploiting the mechanism we discovered to soften T-cells, we could accelerate vaccine responses so a patient won’t need multiple boosters and months of waiting to get full immunity. Or we could stiffen up T-cells to prevent the body from rejecting transplanted organs.”
“Cytoskeletal Adaptivity Regulates T-cell Receptor Signaling,” Science Signaling, March 7, 2017