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When it comes to distinguishing a healthy cell from an infected one that needs to be destroyed, the immune system’s killer T cells sometimes make mistakes. This discovery, described today in the journal eLife, upends a long-held belief among scientists that T cells were nearly perfect at discriminating friend from foe. The results may point to new ways to treat autoimmune diseases that cause the immune system to attack the body, or lead to improvements in cutting-edge cancer treatments.

colourized 3d electron micrograph of T cell

It is widely believed that T cells can discriminate perfectly between infected cells and healthy ones based on how tightly they are able to bind to molecules called antigens on the surface of each. They bind tightly to antigens derived from viruses or bacteria, but less tightly to our own antigens on normal cells. But recent studies by scientists looking at autoimmune diseases suggest that T cells can attack otherwise normal cells if they express unusually large numbers of our own antigens, even though these bind only weakly.

 

We set out to resolve this discrepancy between the idea that T cells are near perfect at discriminating between healthy and infected cells based on the antigen binding strength, and clinical results that suggests otherwise.
- Johannes Pettmann

Co-first author Johannes Pettmann, a DPhil student based at the Sir William Dunn School of Pathology and the Davis lab at the MRC Weatherall Institute of Molecular Medicine, added “We did this by very precisely measuring the binding strength of different antigens.”

The team measured exactly how tightly receptors on T cells bind to a large number of different antigens, and then measured how T cells from healthy humans responded to cells loaded with different amounts of these antigens. “Our methods, combined with computer modelling, showed that the T cell’s receptors were better at discrimination compared to other types of receptors,” says co-first author Anna Huhn, also a DPhil student at the Sir William Dunn School of Pathology. “But they weren’t perfect – their receptors compelled T cells to respond even to antigens that showed only weak binding.”

Read the full story on the Radcliffe Department of Medicine website.

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