Multidimensional Analyses of Proinsulin Peptide-specific Regulatory T Cells Induced by Tolerogenic Dendritic Cells

Induction of antigen-specific regulatory T cells (Tregs) in vivo is the holy grail of current immune-regulating therapies in autoimmune diseases, such as type 1 diabetes. Tolerogenic dendritic cells (tolDCs) generated from monocytes by a combined treatment with vitamin D and dexamethasone (marked by CD52hi and CD86lo expression) induce antigen-specific Tregs. We evaluated the phenotypes of these Tregs using high-dimensional mass cytometry to identify a surface-based T cell signature of tolerogenic modulation. Naïve CD4+ T cells were stimulated with tolDCs or mature inflammatory DCs pulsed with proinsulin peptide, after which the suppressive capacity, cytokine production and phenotype of stimulated T cells were analysed. TolDCs induced suppressive T cell lines that were dominated by a naïve phenotype (CD45RA+CCR7+). These naïve T cells, however, did not show suppressive capacity, but were arrested in their naïve status. T cell cultures stimulated by tolDC further contained memory-like (CD45RA-CCR7-) T cells expressing regulatory markers Lag-3, CD161 and ICOS. T cells expressing CD25lo or CD25hi were most prominent and suppressed CD4+ proliferation, while CD25hi Tregs also effectively supressed effector CD8+ T cells. We conclude that tolDCs induce antigen-specific Tregs with various phenotypes. This extends our earlier findings pointing to a functionally diverse pool of antigen-induced and specific Tregs and provides the basis for immune-monitoring in clinical trials with tolDC.

Resources

• Publisher
• Preprint
• Supplement
• Data

Citation

BibTeX

@article{ bib:2019_JofAutoimmunity,
    author = {Jessica S. Suwandi and Sandra Laban and Kincso Vass and Antoinette Joosten and Vincent van Unen and Boudewijn Lelieveldt and Thomas H{\"o}llt and Jaap Jan Zwaginga and Tatjana Nikolic and Bart O.Roep},
    title = { Multidimensional Analyses of Proinsulin Peptide-specific Regulatory T Cells Induced by Tolerogenic Dendritic Cells },
    journal = { Journal of Autoimmunity },
    volume = { 107 },
    pages = { 102361 },
    year = { 2020 },
    doi = { 10.1016/j.jaut.2019.102361 },
}