For the first time, immunologists from The University of Texas at Austin have captured on video what happens when T-cells – the contract killers of the immune system, responsible for wiping out bacteria and viruses – undergo a type of assassin-training program before they get unleashed in the body. A new imaging technique that allowed for the videos, described today in the journal Nature Communications, holds promise for the fight against autoimmune disorders such as Type 1 diabetes.
One of the human body's most potent weapons against many diseases is the T-cell, but in people with autoimmune disorders, T-cells also wreak havoc by mistaking normal cells for invaders and attacking healthy parts of the body.
"T-cells have the daunting task of recognizing and fighting off all of the diverse pathogens that we encounter throughout our lives, while avoiding attacking our own healthy tissue," said associate professor Lauren Ehrlich, one of the authors of the study. "These cells mature in the thymus, an organ just above the heart, where they 'get educated' to not attack the body."
Ehrlich and postdoctoral researcher Jessica Lancaster captured video of this educational process in a mouse thymus. Using a pair of powerful lasers that fire in short pulses and scan through a slice of live tissue every 15 seconds to reconstruct the positions, movements and intracellular signaling of cells, they observed that as T-cells develop, other cells in the thymus help them to encounter all sorts of ordinary human proteins that, later on, the T-cells will need to ignore in order to avoid attacking other parts of the body. The researchers learned more about how different types of cells work together in the thymus to perform the safety tests and, in the event a T-cell fails, trigger it to self-destruct.
Ehrlich says studying T-cells with this new imaging technique holds promise for improvements for human health that will depend on a better understanding of what's happening in the thymus. For example, patients who received bone-marrow transplants endure weeks or months with suppressed immune systems and a higher risk for developing autoimmune disorders, and people with Type 1 diabetes have T-cells that often attack the cells in the pancreas that produce insulin.
This work was supported by the National Institute of Allergy and Infectious Diseases and the Cancer Prevention and Research Institute of Texas; Ehrlich is a CPRIT scholar.
To see more videos of T-cells being tested for autoreactivity by other cells in the thymus, go to: https://utexas.box.com/s/tm28bg43ufntpm8mz2gklo1y60yme0o3
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Each T-cell in your body has receptors tuned to react to specific proteins. During the testing phase, two types of cells—called medullary thymic epithelial cells (mTECs) and dendritic cells (DCs)—display chopped up bits of normal proteins from the body, called self antigens. If a T-cell touches one of these cells and its receptors happen to match the self antigen displayed, calcium levels spike within the T-cell. This signal indicates the T-cell has failed the safety check. Left to roam the body, it would attack the body's own cells. Fortunately, in most cases, this calcium signal triggers the T-cell to self destruct.
"We didn't really understand the relative contributions of these two types of cells in helping the T-cells develop tolerance," Ehrlich said, "and without developing this way of imaging, this question really couldn't be addressed very well."
Videos produced with the new method show individual T-cells interacting with DCs and mTECs and the calcium signals that sometimes arise, indicating an autoreactive T-cell. This is the first time anyone has been able to directly image this process. The researchers discovered that DCs often pick up self antigens produced by mTECs and display them to developing T-cell. This appears to make the testing process faster and more efficient. That's a bigger role for DCs in this testing than was previously thought.
"Even though the mTECs are producing the self antigens, it's the DCs that are more often driving T-cells to self destruct," Ehrlich said. "That's not what people expected."
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