Abstract
T cells use their T-cell receptors (TCRs) to discriminate between lower-affinity self and higher affinity non-self pMHC antigens. Although the discriminatory power of the TCR is widely believed to be near-perfect, technical difficulties have hampered efforts to precisely quantify it. Here, we describe a method for measuring very low TCR/pMHC affinities, and use it to measure the discriminatory power of the TCR, and the factors affecting it. We find that TCR discrimination, although enhanced compared with conventional cell-surface receptors, is imperfect: primary human T cells can respond to pMHC with affinities as low as KD ~ 1 mM. The kinetic proofreading mechanism fit our data, providing the first estimates of both the time delay (2.8 s) and number of biochemical steps (2.67) that are consistent with the extraordinary sensitivity of antigen recognition. Our findings explain why self pMHC frequently induce autoimmune diseases and anti-tumour responses, and suggest ways to modify TCR discrimination.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
This revised manuscript is a combination of two separate manuscripts we initially posted on bioRxiv. Both manuscripts came to the same conclusion using different methods and based on feedback from colleagues, we have decided to combine both manuscripts. The two initial manuscripts that have been combined to make this manuscript are 1) the previous version of this manuscript (Huhn et al (2020)) and 2) Pettmann et al (2020) bioRxiv, https://doi.org/10.1101/2020.11.14.382630
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