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Circulating gluten-specific, but not CMV-specific, CD39+ regulatory T cells have an oligoclonal TCR repertoire.

ABSTRACT: Objectives:Understanding the T cell receptor (TCR) repertoire of regulatory CD4+ T-cell (Treg) populations is important for strategies aiming to re-establish tolerance in autoimmune diseases. We studied circulating deamidated gluten-epitope-specific CD39+ Tregs in patients with coeliac disease following an oral gluten challenge, and we used cytomegalovirus (CMV)-specific CD39+ Tregs from healthy controls as a comparator population. Methods:We used the OX40 assay to isolate antigen-specific Tregs by induced surface co-expression of CD25, OX40 and CD39. RACE PCR amplification and Sanger sequencing of the TCR ? chain were used to analyse repertoire diversity. Results:We found that, following oral gluten challenge, circulating gluten-specific CD39+ Tregs had an oligoclonal TCR repertoire that contained public clonotypes. Conversely, the TCR repertoire of CMV-epitope-specific CD39+ Tregs from healthy controls was polyclonal. Discussion:These data indicate that a biased TCR repertoire is not inherent to CD39+ Tregs, and, in this case, is apparently driven by the HLA-DQ2.5-restricted deamidated gluten peptide in coeliac disease patients. Conclusion:This is the first assessment of the TCR repertoire within circulating human Tregs specific for foreign antigen. These data enhance our understanding of antigen-specific CD4+ responses in the settings of chronic inflammation and infection and may help guide immunomonitoring strategies for CD4+ T cell-based therapies, particularly for coeliac disease.

SUBMITTER: Cook L

PROVIDER: S-EPMC6955237 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Circulating gluten-specific, but not CMV-specific, CD39<sup>+</sup> regulatory T cells have an oligoclonal TCR repertoire.

Cook Laura L Munier C Mee Ling CML Seddiki Nabila N Hardy Melinda Y MY Anderson Robert P RP Zaunders John J Tye-Din Jason A JA Kelleher Anthony D AD van Bockel David D

Clinical & translational immunology 20200112 1

<h4>Objectives</h4>Understanding the T cell receptor (TCR) repertoire of regulatory CD4<sup>+</sup> T-cell (Treg) populations is important for strategies aiming to re-establish tolerance in autoimmune diseases. We studied circulating deamidated gluten-epitope-specific CD39<sup>+</sup> Tregs in patients with coeliac disease following an oral gluten challenge, and we used cytomegalovirus (CMV)-specific CD39<sup>+</sup> Tregs from healthy controls as a comparator population.<h4>Methods</h4>We used ...[more]

PMID: 31956412

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Project description:BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed variants escaping neutralization antibody immunity established against the original virus. An understanding of broad-spectrum adaptive immunity, including CD8+ T cell immunity to wide range of epitopes, could help translational efforts to improve coronavirus disease 2019 (COVID-19) prevention and therapy. However, there have been few direct studies in which such immunity exists in a population.MethodsWe selected SARS-CoV-2-conserved structural peptides that are not prone to mutation as antigens for broad-spectrum CD8+ T cell immunity. Peripheral blood mononuclear cells (PBMCs) from unexposed healthy donors were stimulated with these peptides in vitro and CD8+ T cell-specific response was monitored. The conserved peptide-specific CD8+ T cells were sorted for T cell receptor (TCR) repertoire sequencing. The presence of specific complementary determining region 3 (CDR3) clones was analyzed in a healthy cohort.ResultsFor each structural protein, including S, E, M, N, the conserved peptides could potentially provide the largest number of major histocompatibility complex-I (MHC-I) epitopes in the Oriental and Caucasian populations. For conserved peptides from spike (S), envelope (E), membrane (M), nucleocapsid (N) proteins, we found that there were no cross-reactive memory T cells in the unexposed individuals. Instead, their T cells contain naïve TCR repertoire recognizing these conserved peptides. Using TCR sequencing and CDR3 clustering for the conserved peptides specific T cells, we found that the recovered patients had a higher proportion of TCR repertoire similar with that of specific CD8+ T cells in unexposed individuals. Meanwhile, CDR3 clones of the above T cells were widely present in the healthy population.ConclusionsThis study provides evidence of broad-spectrum SARS-CoV-2 specific CD8+ TCR repertoire in unexposed healthy population, which is implicated in the development and implementation of broad-spectrum vaccines against COVID-19.

Dataset Information

Circulating gluten-specific, but not CMV-specific, CD39+ regulatory T cells have an oligoclonal TCR repertoire.

Publications

Circulating gluten-specific, but not CMV-specific, CD39<sup>+</sup> regulatory T cells have an oligoclonal TCR repertoire.

Similar Datasets

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