Salk scientists used light-sheet superresolution imaging to capture the rearrangement of T-cell receptors from nanometer-scale protein islands (left) to micrometer-scale microclusters (right) after T-cell activation in mouse lymph nodes. [Salk Institute]
Salk scientists used light-sheet superresolution imaging to capture the rearrangement of T-cell receptors from nanometer-scale protein islands (left) to micrometer-scale microclusters (right) after T-cell activation in mouse lymph nodes. [Salk Institute]

Scientists from the Salk Institute say they have imaged how vital receptors on the surface of T-cells bundle together when activated to fight an invading pathogen. The study (“Superresolution Imaging Reveals Nanometer- and Micrometer-Scale Spatial Distributions of T-Cell Receptors in Lymph Nodes”), published in PNAS, and reportedly the first to visualize this process in lymph nodes, could help scientists better understand how to turn the immune system's activity up or down to treat autoimmune diseases, infections, or even cancer.

“We had seen these receptors cluster and reposition in cultured cells that were artificially stimulated in the lab, but we've never seen their natural arrangements in lymph nodes until now,” says senior author Björn Lillemeier, Ph.D., an associate professor in Salk's Nomis Laboratories for Immunobiology and Microbial Pathogenesis and the Waitt Advanced Biophotonics Center.

Activated T-cells switch on cellular pathways that help the body both actively seek out and destroy the antigens (e.g., virus, bacterium, or cancer cell) and remember it for the future. In the past, by looking at T-cell receptors embedded in isolated cells under the microscope, researchers discovered that the receptors are arranged in clusters of protein islands that merge when the cells are activated.

Dr. Lillemeier wanted more detail on how the receptors are arranged in tissue and how that arrangement might change when the T-cells are activated in living hosts. The team used a superresolution microscope developed in the laboratory of co-senior author Hu Cang, Ph.D., assistant professor at Salk's Waitt Advanced Biophotonics Center and holder of the Frederick B. Rentschler Developmental Chair. This microscopy approach, called light-sheet direct stochastic optical reconstruction microscopy (dSTORM), let the researchers watch T-cell receptors in the membranes of T-cells in mouse lymph nodes at a resolution of approximately 50 nanometers.

The new imagery confirmed the previous observation that protein islands of T-cell receptors merge into larger microclusters when T-cells are activated. But it also showed that, before cells are activated, the protein islands are already arranged in groups, dubbed “territories” by Dr. Lillemeier's team. “The preorganization on the molecular level basically turns the T-cell into a loaded gun,” notes Dr. Lillemeier.

The organization of surface receptors enables T-cells to launch fast and effective immune response against antigens. Understanding how the molecular organization mediates the sensitivity of T-cell responses could help researchers make the immune system more or less sensitive. In the case of autoimmune diseases, clinicians would like to turn down the immune system's activity, whereas turning up the activity could help fight infections or cancers.

The research could also have implications for understanding other receptors in the body that have a wide range of functions both within and outside the immune system. “We think that most receptors on the surfaces of cells are organized like this,” says Ying Hu, Ph.D., first author and postdoctoral researcher at the Salk Institute.








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