Is the exquisite specificity of lymphocytes generated by thymic selection or due to evolution?

Rob J De Boer*, Can Kesmir, Alan S Perelson, José A M Borghans

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

We have previously argued that the antigen receptors of T and B lymphocytes evolved to be sufficiently specific to avoid massive deletion of clonotypes by negative selection. Their optimal 'specificity' level, i.e., probability of binding any particular epitope, was shown to be inversely related to the number of self-antigens that the cells have to be tolerant to. Experiments have demonstrated that T lymphocytes also become more specific during negative selection in the thymus, because cells expressing the most crossreactive receptors have the highest likelihood of binding a self-antigen, and hence to be tolerized (i.e., deleted, anergized, or diverted into a regulatory T cell phenotype). Thus, there are two -not mutually exclusive- explanations for the exquisite specificity of T cells, one involving evolution and the other thymic selection. To better understand the impact of both, we extend a previously developed mathematical model by allowing for T cells with very different binding probabilities in the pre-selection repertoire. We confirm that negative selection tends to tolerize the most crossreactive clonotypes. As a result, the average level of specificity in the functional post-selection repertoire depends on the number of self-antigens, even if there is no evolutionary optimization of binding probabilities. However, the evolutionary optimal range of binding probabilities in the pre-selection repertoire also depends on the number of self-antigens. Species with more self antigens need more specific pre-selection repertoires to avoid excessive loss of T cells during thymic selection, and hence mount protective immune responses. We conclude that both evolution and negative selection are responsible for the high level of specificity of lymphocytes.

Original languageEnglish
Article number1266349
Number of pages10
JournalFrontiers in Immunology
Volume15
DOIs
Publication statusPublished - 25 Mar 2024

Bibliographical note

Publisher Copyright:
Copyright © 2024 De Boer, Kesmir, Perelson and Borghans.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Portions of this work were performed under the auspices of the U. S. Department of Energy under contract 89233218CNA000001 and supported by NIH grant R01-AI028433 (ASP).

FundersFunder number
U.S. Department of Energy89233218CNA000001
U.S. Department of Energy
National Institutes of HealthR01-AI028433
National Institutes of Health

    Keywords

    • Autoantigens
    • B-Lymphocytes
    • Epitopes
    • T-Lymphocytes, Regulatory
    • Thymus Gland

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