Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom; Radcliffe Department of Medicine, Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom; Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
Daniel B Wilson
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom; Boston University, Department of Mathematics and Statistics, Boston, United States
Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
Simon J Davis
Radcliffe Department of Medicine, Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
T cells use their T cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity non-self peptides presented on major histocompatibility complex (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.
