Broad cross-reactivity of the T-cell repertoire achieves specific and sufficiently rapid target searching

TL;DR

This study quantifies T-cell receptor cross-reactivity, revealing a broad spectrum that balances rapid target searching with unbinding efficiency, crucial for adaptive immunity.

Contribution

It introduces a string model to quantify T-cell receptor cross-reactivity and analyzes its impact on target searching efficiency in adaptive immunity.

Findings

T-cell receptors show broad cross-reactivity, reactive to up to 1,000 peptides.

Broad cross-reactivity balances rapid target screening and unbinding penalties.

Natural T-cell repertoire's cross-reactivity optimizes immune response efficiency.

Abstract

The molecular recognition of T-cell receptors is the hallmark of the adaptive immunity. Given the finiteness of the T-cell repertoire, individual T-cell receptors are necessary to be cross-reactive to multiple antigenic peptides. In this study, we quantify the variability of the cross-reactivity by using a string model that estimates the binding affinity between two sequences of amino acids. We examine sequences of 10,000 human T-cell receptors and 10,000 antigenic peptides, and obtain a full spectrum of cross-reactivity of the receptor-peptide binding. Then, we find that the cross-reactivity spectrum is broad. Some T cells are reactive to 1,000 peptides, but some T cells are reactive to only one or two peptides. Since the degree of cross-reactivity has a correlation with the (un)binding affinity of receptors, we further investigate how the broad crossreactivity affects the target searching of T cells. High cross-reactive T cells may not require many trials for searching correct targets, but they may spend long time to unbind from incorrect targets. In contrast, low cross-reactive T cells may not spend long time to ignore incorrect targets, but they require many trials for screening correct targets. We evaluate this hypothesis, and show that the broad cross-reactivity of the natural T-cell repertoire can balance the trade-off between the rapid screening and unbinding penalty.