An Arthritis-Suppressive and Treg Cell-Inducing CD4+ T Cell Epitope is Functional in the Context of HLA-Restricted T Cell Responses

Charlotte De Wolf, Ruurd Van Der Zee, Ineke Den Braber, Tibor Glant, Bernard Maill??re, Emmanuel Favry, Menno Van Lummel, Frits Koning, Aad Hoek, Irene Ludwig, Willem Van Eden, Femke Broere*

*Corresponding author for this work

    Research output: Chapter in Book/Report/Conference proceedingChapterAcademicpeer-review

    Abstract

    Previously, we have shown that mycobacterial heat shock protein 70 (HSP70)-derived peptide B29 induces B29-specific regulatory T cells, which suppressed experimental arthritis in mice by cross-recognition of their mammalian HSP70 homologs (1). The aim of this study is to characterize the B29 binding and specific CD4(+) T cell responses in the context of human MHC molecules (HLA). Binding of B29 peptide and its mammalian homologs to HLA molecules was examined with competitive binding assays. The effect of B29 immunization was assessed in proteoglycan-induced arthritis in HLA-DQ8 transgenic mice, followed by ex vivo restimulation with B29 to examine the T cell response. Human PBMC were used to investigate the presence of B29-specific T cells with immunoregulatory potential. We found a high to moderate binding affinity for multiple HLA-DR and HLA-DQ molecules, including those highly associated with rheumatoid arthritis. This binding was functional, as B29 immunization resulted in suppression of arthritis and T cell responses in HLA-DQ8 transgenic mice. In humans, we demonstrated the presence and expansion of B29-specific CD4(+) T cells, which were cross-reactive with the mammalian homologs. With HLA-DR4(+) tetramers specific for B29 or mB29b we showed expansion of cross-reactive T cells, especially the human CD4(+) CD25(+) FoxP3(+) T cell population after in vitro stimulation with B29. These results demonstrated a conserved fine-specificity and functionality of the B29-induced regulatory T cell responses in the context of the human MHC. Based on these findings, a translational path of the B29 experimental findings into a clinical immunomodulatory therapeutic approach comes within reach. This article is protected by copyright. All rights reserved.
    Original languageEnglish
    Title of host publicationArthritis and Rheumatology
    PublisherJohn Wiley and Sons Inc.
    Pages639-647
    Number of pages9
    ISBN (Print)8133815541
    DOIs
    Publication statusPublished - 1 Mar 2016

    Publication series

    NameArthritis and Rheumatology
    Number3
    Volume68

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