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. 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.

Progressive enhancement of kinetic proofreading in T cell antigen discrimination from receptor activation to DAG generation

“…Our results suggest a kinetic proofreading system that starts at the level of receptor activation and continues across multiple spatially segregated signaling complexes, with downstream signaling complexes resetting slower than receptor-level signaling complexes. Such a system would allow high concentration of antigens with intermediate binding lifetimes to activate T cells, while still responding to rare long binding antigens and filtering out short binding antigens, which is consistent with TCR cooperativity postulated in tissue homeostasis and autoimmunity ( Cameron et al, 2013 ; Goyette et al, 2022 ; Korem Kohanim et al, 2020 ; Lin et al, 2019 ; Pettmann et al, 2021 ; Wang et al, 2020 ).…”

Progressive enhancement of kinetic proofreading in T cell antigen discrimination from receptor activation to DAG generation

“…Our results suggest a kinetic proofreading system that starts at the level of receptor activation and continues across multiple spatially segregated signaling complexes, with downstream signaling complexes resetting slower than receptor-level signaling complexes. Such a system would allow high concentration of antigens with intermediate binding lifetimes to activate T cells, while still responding to rare long-binding antigens and filtering out short-binding antigens, which is consistent with TCR cooperativity postulated in tissue homeostasis and autoimmunity (Cameron et al, 2013;Goyette et al, 2020;Korem Kohanim et al, 2020;Lin et al, 2019;Pettmann et al, 2021;Wang et al, 2020).…”

“…McKeithan postulated that a kinetic proofreading system with slower reset rates for downstream events compared to upstream signaling events would respond to true cognate-antigen binding events a higher percentage of the time while still ignoring weak self-antigen binding events (McKeithan, 1995). Recently, Pettman et al modeled how slower resetting of terminal signaling complexes could account for fractional steps in their measurements of the number of proofreading steps (Pettmann et al, 2021). We measured slower dissociation of downstream LAT clusters through a slow multistep process compared to the upstream events of ligand binding and Zap-70 recruitment which followed a more rapid single step reset process (Fig.…”

Know thy immune self and non‐self: Proteomics informs on the expanse of self and non‐self, and how and where they arise

“…Accounting for this interaction is critical as the TCR is very sensitive: that is, the receptor can recognize and respond to one‐to‐ten molecules of an antigen [ 84 , 284 ]. As well, it can discriminate between two peptides differing by a methylene group or a methyl and a hydroxyl group in an accessory anchor—for example, H4 minor histocompatibility alloantigens [ 86 , 285 , 286 ]. This sensitivity coupled with a rather loose ’recognition logic‘ and micro‐to‐milli‐molar binding affinity with which the TCR interfaces its cognate antigen—the p/MHC—is thought to make the TCR highly cross reactive [ 286 ‐ 290 ].…”

“…As well, it can discriminate between two peptides differing by a methylene group or a methyl and a hydroxyl group in an accessory anchor—for example, H4 minor histocompatibility alloantigens [ 86 , 285 , 286 ]. This sensitivity coupled with a rather loose ’recognition logic‘ and micro‐to‐milli‐molar binding affinity with which the TCR interfaces its cognate antigen—the p/MHC—is thought to make the TCR highly cross reactive [ 286 ‐ 290 ]. A case in point is the recognition of ∼100 different peptides by an H4 b ‐reactive CD8 + T cell line [ 291 ]—yet the 100 mimotopes so identified did not contain the actual epitope [ 86 , 285 ].…”