Short‐term cytokine stimulation reveals regulatory T cells with down‐regulated Foxp3 expression in human peripheral blood |
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| Authors: | Paula Tabares Susanne Berr Daniela Langenhorst Birgit Sawitzki Ineke ten Berge Hans‐Peter Tony Thomas Hünig |
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| Affiliation: | 1. Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany;2. Institute of Medical Immunology, Charité University Medicine, Berlin, Germany;3. Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;4. Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany |
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| Abstract: | The identification of regulatory T cells (Treg cells) in human peripheral blood is an important tool in diagnosis, research, and therapeutic intervention. As compared to lymphoid tissues, the frequencies of circulating Treg cells identified as CD4+CD25+Foxp3+ are, however, low. We here show that many of these cells remain undetected due to transient down regulation of Foxp3, which rapidly decays in the absence of cytokine‐mediated STAT5 signals. Short‐term incubation of PBMCs or isolated CD4+ T cells, but not of lymph node cells, with IL‐2, ‐7, or ‐15 more than doubles the frequency of Foxp3+CD25+ among CD4+ T cells detectable by flow cytometry. This increase is not due to cell division but to upregulation of both proteins. At the same time, the uncovered Treg cells up‐regulate CD25 and down‐regulate CD127, making them accessible to viable cell sorting. “Latent” Treg cells have a demethylated FOXP3 TSDR sequence, are enriched in naïve, non‐cycling cells, and are functional. The confirmation of our findings in RA and SLE patients shows the feasibility of uncovering latent Treg cells for immune monitoring in clinical settings. Finally, our results suggest that unmasking of latent Treg cells contributes to the increase in circulating CD4+CD25+Foxp3+ cells reported in IL‐2 treated patients. |
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| Keywords: | Foxp3 IL‐2 Latent treg Regulatory T cells Treg identification |
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