Until now, the ability of T lymphocytes to distinguish between healthy and infected cells was deemed to be near perfect. New research findings published in eLife show this is not the case.
T lymphocytes use TCRs (T cell receptors) to establish the difference between the body’s own cells, whose recognizable cell surface peptide-signposts or antigens bind to it weakly, and infected cells where foreign peptides presented atop major histocompatibility complexes (pMHC) signposts bind to TCRs with strong affinity.
The scientists show that although the TCR discrimination power is much higher compared to other cell surface receptors, it is imperfect at telling healthy and infected cells apart.
In the article titled “The discriminatory power of the T cell receptor,” the scientists describe a new surface plasmon resonance method for measuring very low TCR/pMHC affinities and use it to measure the discriminatory power of the TCR and factors affecting it.
These results may lead to new ways to treat autoimmune diseases where the immune system attacks its own cells, or direct improvements in cancer treatments.
Recent studies by scientists looking at autoimmune diseases suggest that T cells can attack otherwise normal cells if they express unusually large numbers of “self” antigens, even though these bind TCRs 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,” says Johannes Pettmann, a DPhil student at the Sir William Dunn School of Pathology and Radcliffe Department of Medicine, University of Oxford, U.K. and co-first author on the study. “We did this by very precisely measuring the binding strength of different antigens.”
The team measured how tightly TCRs bind to many 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 modeling, showed that the T cell’s receptors were better at discrimination compared to other types of receptors,” says Anna Huhn, also a DPhil student at the Sir William Dunn School of Pathology, University of Oxford and co-first author on the study. “But they weren’t perfect—their receptors compelled T cells to respond even to antigens that showed only weak binding.”
“This finding completely changes how we view T cells,” says Enas Abu-Shah, PhD, postdoctoral fellow at the Kennedy Institute and the Sir William Dunn School of Pathology, University of Oxford, and also a co-first author on the study. “Instead of thinking of them as near-perfect discriminators of the antigen binding strength, we now know that they can respond to normal cells that simply have more of our own weakly binding antigens.”
Technical issues with measuring the strength of T cell receptor binding in previous studies likely led to the mistaken conclusion that T cells are perfect discriminators, the authors note, highlighting the importance of using more precise protocols.
“Our work suggests that T cells might begin to attack healthy cells if those cells produce abnormally high numbers of antigens,” says Omer Dushek, PhD, associate professor at the Sir William Dunn School of Pathology, University of Oxford, a Senior Research Fellow in Basic Biomedical Sciences at the Wellcome Trust, U.K. and senior author on the study.
“This contributes to a major paradigm shift in how we think about autoimmunity, because instead of focusing on defects in how T cells discriminate between antigens, it suggests that abnormally high levels of our own antigens may be responsible for the mistaken autoimmune T-cell response. On the other hand, this ability could be helpful to kill cancer cells that mutate to express abnormally high levels of our antigens,” says Dushek.
The finding opens new avenues of research to improve the discrimination abilities of T cells, which could reduce autoimmune side-effects of many T-cell-based therapies without reducing the ability of these cells to attack malignant cells.