How a well-adapted immune system is organized

TL;DR

This paper presents a theoretical framework for understanding how the immune system optimally organizes its receptor repertoire to minimize infection costs, considering pathogen diversity and cross-reactivity.

Contribution

It introduces a general model predicting immune receptor distributions based on pathogen statistics and receptor cross-reactivity, advancing understanding of immune system organization.

Findings

Optimal repertoires have more receptors for rare antigens.

Individuals with similar infections have diverse but cross-reactive repertoires.

Repertoire dynamics involve competitive binding and selective amplification.

Abstract

The repertoire of lymphocyte receptors in the adaptive immune system protects organisms from diverse pathogens. A well-adapted repertoire should be tuned to the pathogenic environment to reduce the cost of infections. We develop a general framework for predicting the optimal repertoire that minimizes the cost of infections contracted from a given distribution of pathogens. The theory predicts that the immune system will have more receptors for rare antigens than expected from the frequency of encounters; individuals exposed to the same infections will have sparse repertoires that are largely different, but nevertheless exploit cross-reactivity to provide the same coverage of antigens; and the optimal repertoires can be reached via the dynamics of competitive binding of antigens by receptors, and selective amplification of stimulated receptors. Our results follow from a tension between the statistics of pathogen detection, which favor a broader receptor distribution, and the effects of cross-reactivity, which tend to concentrate the optimal repertoire onto a few highly abundant clones. Our predictions can be tested in high throughput surveys of receptor and pathogen diversity.