Identifying feasible operating regimes for early T-cell recognition: The speed, energy, accuracy trade-off in kinetic proofreading and adaptive sorting

Abstract

In the immune system, T cells can quickly discriminate between foreign and self ligands with high accuracy. There is evidence that T-cells achieve this remarkable performance utilizing a network architecture based on a generalization of kinetic proofreading (KPR). KPR-based mechanisms actively consume energy to increase the specificity beyond what is possible in equilibrium. An important theoretical question that arises is to understand the trade-offs and fundamental limits on accuracy, speed, and dissipation (energy consumption) in KPR and its generalization. Here, we revisit this question through numerical simulations where we simultaneously measure the speed, accuracy, and energy consumption of the KPR and adaptive sorting networks for different parameter choices. Our simulations highlight the existence of a “feasible operating regime” in the speed-energy-accuracy plane where T-cells can quickly differentiate between foreign and self ligands at reasonable energy expenditure. We give general arguments for why we expect this feasible operating regime to be a generic property of all KPR-based biochemical networks and discuss implications for our understanding of the T cell receptor circuit.

Slow phosphorylation of a tyrosine residue in LAT optimizes T cell ligand discrimination

“…T cell responses, mediated by T cell antigen receptors (TCRs), are remarkable for their high sensitivity, exquisite specificity, and rapidity 1 . T cells can be activated in response to very few foreign peptide-major histocompatibility complex (pMHC) ligands (one to ten) [2][3][4] , with a small error rate (10 −4 to 10 −6 ) 5,6 and rapid response time (seconds to a few minutes) 7 . This rapid and highly accurate responsiveness allows T cells to detect peptides derived from foreign pathogens or abnormal cells early and efficiently without reacting to self-tissues.…”

Allostery and Kinetic Proofreading

“…This is in contrast to the typical involvement of several energy consumption instances in multistep proofreading schemes which manage to beat the Hopfield limit of fidelity, as, for example, in the cases of the T-cell or MAPK activation pathways which require multiple phosphorylation reactions. 5,6,34 Our finding therefore suggests the possibility of achieving several proofreading realizations with a single energy consuming step by leveraging the presence of multiple inactive intermediates intrinsically available to allosteric molecules. We would like to mention here that the presence of a similar feature was also experimentally demonstrated recently for the ribosome which was shown to use the free energy of a single GTP hydrolysis to perform proofreading twice after the initial tRNA selection -first, at the EF-Tu • GDP-bound inactive state and second, at the EF-Tu-free active state.…”

Proofreading through spatial gradients

“…The nonequilibrium mechanism called kinetic proofreading [1,2] is used for reducing the error rates of many biochemical processes important for cell function (e.g., DNA replication [3], transcription [4], translation [5,6], signal transduction [7], or pathogen recognition [8][9][10]). Proofreading mechanisms operate by inducing a delay between substrate binding and product formation via intermediate states for the enzyme-substrate complex.…”

“…(a) The traditional proofreading scheme with multiple biochemically distinct intermediates, transitions between which are typically accompanied by energyconsuming reactions. The T-cell activation mechanism with successive phosphorylation events is used for demonstration [8,10]. (b) The spatial proofreading scheme where the delay between binding and catalysis is created by constraining these events to distinct physical locations.…”