The discriminatory power of the T cell receptor

Abstract

T cells use their T-cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity non-self pMHC antigens. The strength of this discrimination and the mechanisms that produce it remain controversial. Although a large number of mouse and human TCRs have now been characterised, they have not been used to precisely quantitate discrimination. Here, we systematically quantify the discrimination of TCRs using a discrimination power (α). Early influential studies on three mouse TCRs suggested that discrimination was nearly perfect (α ~ 9.0). In striking contrast, our analysis of published data on other mouse and human TCRs, and more recent data on the original mouse TCRs, produced significantly lower discrimination (α = 2.0). Although not perfect, the discriminatory power of TCR was greater than that of conventional receptors such as cytokine receptors, GPCRs, RTKs, and CARs (α ≤ 1). The revised discriminatory power of the TCR is readily explained by a kinetic proofreading mechanisms, and accounts for the ability of low affinity self-antigens to stimulate autoimmune and anti-tumour T cell responses.

T cells exhibit unexpectedly low discriminatory power and can respond to ultra-low affinity peptide-MHC ligands

“…The discrepancy between previous work (4–8, 19, 25, 27) and other human and mouse TCRs (34), including the present work, is likely a result of inaccurate SPR affinity measurements. In addition to temperature and protein aggregation (see Introduction), we have found that extrapolating the K D from non-saturating binding curves reduces precision and underestimates the K D .…”

“…The level of antigen discrimination we report in this study and in an analysis of the literature (34) can be explained by the standard KP model. A number of studies, including work from our lab, have reported additional mechanisms beyond the standard KP model to explain the higher level of discrimination originally reported (17–32).…”

“…Quantifying the discrimination power produces values of 1.9–2.1 using APCs. In a separate analysis of the published literature, we found similar discrimination powers for other human and mouse TCRs (2.0 with 95% CI of 1.5-2.4) that were significantly lower than those for the original murine TCR data (~9.0) (34). The discrimination power we report is significantly higher than the baseline predicted by a receptor occupancy model (1.0) and can readily be explained by a KP mechanism.…”

“…To quantify the non-linearity, we fit the potency plots with a power law, where α measures the discrimination power (slope on the log-log plot) and C measures sensitivity (y-intercept on the log-log plot). The baseline discrimination power provided by an occupancy model is α = 1 and analysis of the original mouse TCR data produces α ~ 9 (34). Although higher than baseline, we found surprisingly low discrimination powers (1.8–2.1), that were similar for naïve, memory, and blasted T cells and for both the 1G4 and A6 TCRs (Figure 2K).…”

“…These other TCRs appear to exhibit a more graded loss of T cell responses as the affinity decreases (e.g. 1G4 TCR (31), B3K506 TCR (32), and 1E6 TCR (33); see also Huhn et al (34)). Therefore, there is an apparent discrepancy in the strength of discrimination between studies.…”