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

Jessica S. Suwandi, Sandra Laban, Kincso Vass, Antoinette Joosten, Vincent van Unen, Boudewijn P. F. Lelieveldt, Thomas Höllt, Jaap Jan Zwaginga, Tatjana Nikolic, and Bart O. Roep

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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.

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@article{bib:suwandi:2020,
    author       = { Suwandi, Jessica S. and Laban, Sandra and Vass, Kincso and Joosten, Antoinette and van Unen, Vincent and Lelieveldt, Boudewijn P. F. and Höllt, Thomas and Zwaginga, Jaap Jan and Nikolic, Tatjana and Roep, Bart O. },    
    title        = { Multidimensional Analyses of Proinsulin Peptide-specific Regulatory T Cells Induced by Tolerogenic Dendritic Cells },
    volume       = { 107 },
    year         = { 2020 },
    doi          = { 10.1016/j.jaut.2019.102361 },
    pubmedid     = { 31776056 },
    url          = { https://publications.graphics.tudelft.nl/papers/161 },
}