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ORIGINAL RESEARCH article

Front. Immunol.

Sec. B Cell Biology

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1535826

This article is part of the Research Topic The Human Antibody Repertoire View all 3 articles

Regulatory T cell epitope content in human antibodies decreases during maturation

Provisionally accepted
  • EpiVax, Inc, Providence, Rhode Island, United States

The final, formatted version of the article will be published soon.

    Antibody maturation in the lymphoid follicle produces antibodies with improved binding affinity. This process requires iterative rounds of mutation and B cell expansion, supported by T cells that recognize epitopes presented on the B cell’s MHC-II. In this comprehensive antibody repertoire analysis, we find that established regulatory T cell epitopes (Tregitopes) decline in maturing antibody sequences as somatic hypermutation (SHM) increases, but potential T effector epitopes do not decline. A previous analysis of B cell receptor (BCR)-derived HLA-DR epitopes present in memory antibody repertoires from seven healthy human donors revealed a decrease in donor-specific epitope content with SHM. Moreover, T cell epitope depletion was associated with class-switching and long-term secretion of antibody into serum. Significant depletion of high-affinity germline-encoded epitopes in high SHM sequences was also observed, but the predicted phenotype of T cells responding to the BCR-derived epitopes (regulatory vs. effector) was not previously evaluated. In this follow-on study, we screened a different set of four donor repertoires to investigate the dynamics of donor-specific HLA-DR T cell epitopes and three subsets of T cell epitope content: previously validated T cell epitopes recognized by thymus-derived Tregs (Tregitopes), potentially tolerated T cell epitopes, and potential effector T cell epitopes. Our results show that Tregitope content reduction is correlated with SHM, suggesting that Tregitopes are removed during maturation. Moreover, T cell epitopes that are likely to be tolerated or tolerogenic were also removed with SHM progression. In contrast, potential T effector epitope content increased with SHM. Tregitope depletion occurred in multiple V-gene pair combinations and was the most frequent T cell epitope change. Furthermore, Tregitope content in IgA and IgG sequences was lower and had greater negative correlation with SHM than IgM, indicating that Tregitope removal is likely associated with class-switching. Tregitope depletion was also associated with maturation to plasmablasts. In vitro, representative Tregitopes inhibited CD4+ T cell proliferation. Mutations introduced by SHM altered Tregitope HLA-DR binding affinities. The correlation of Tregitope depletion with increasing SHM implies that the activity of thymus-derived Tregs in immune responses to antibodies is diminished with SHM, maturation, and isotype switching, supporting the generation of anti-idiotype responses.

    Keywords: B cell maturation, Germinal center (GC), somatic hypermutation (SHM), Antibody repertoire, B cell receptor (BCR), HLA-DR T cell epitopes, tregitopes, Regulatory T cell epitopes

    Received: 27 Nov 2024; Accepted: 24 Mar 2025.

    Copyright: © 2025 Gutierrez, Terry, Rosenberg, Martin and De Groot. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Andres H. Gutierrez, EpiVax, Inc, Providence, RI 02909, Rhode Island, United States
    Anne Searls De Groot, EpiVax, Inc, Providence, RI 02909, Rhode Island, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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