@article{430c4da2e11b4dbcbcb2f5869354b91e,
title = "Selective IL-2 responsiveness of regulatory t cells through multiple intrinsic mechanisms supports the use of low-dose IL-2 therapy in type 1 diabetes",
abstract = "Low-dose interleukin-2 (IL-2) inhibited unwanted immune responses in several clinical settings and is currently being tested in patients with type 1 diabetes (T1D). Low-dose IL-2 selectively targets regulatory T cells (Tregs), but the mechanisms underlying this selectivity are poorly understood. We show that IL-2- dependent STAT5 activation in Tregs from healthy individuals and patients with T1D occurred at an ∼10-fold lower concentration of IL-2 than that required by T memory (TM) cells or by in vitro- Activated T cells. This selective Treg responsiveness is explained by their higher expression of IL-2 receptor subunit a (IL-2Ra) and g chain and also endogenous serine/threonine phosphatase protein phosphates 1 and/or 2A activity. Genome-wide profiling identified an IL-2-dependent transcriptome in human Tregs. Quantitative assessment of selected targets indicated that most were optimally activated by a 100-fold lower concentration of IL-2 in Tregs versus CD4+ TM cells. Two such targets were selectively increased in Tregs from T1D patients undergoing low-dose IL-2 therapy. Thus, human Tregs possess an IL-2-dependent transcriptional amplification mechanism that widens their selective responses to low IL-2. Our findings support a model where low-dose IL-2 selectively activates Tregs to broadly induce their IL-2/IL-2R gene program and provide a molecular underpinning for low-dose IL-2 therapy to enhance Tregs for immune tolerance in T1D.",
author = "Aixin Yu and Isaac Snowhite and Francesco Vendrame and Michelle Rosenzwajg and David Klatzmann and Alberto Pugliese and Malek, {Thomas R.}",
note = "Funding Information: Acknowledgments. The authors thank the Flow Cytometry Cores of the Diabetes Research Institute and the Sylvester Comprehensive Cancer Center at the University of Miami, and Oliver Umland, of the University of Miami, for expert help with flow cytometry. Funding. This work was supported by the Diabetes Research Institute Foundation, Hollywood, FL, the Peacock Foundation, Inc., Miami, FL, the Anton E.B. Schefer Foundation, and French state funds managed by the ANR within the Investissements d{\textquoteright}Avenir programme (ANR-11-IDEX-0004-02). Duality of Interest. M.R. and D.K. are inventors on a patent application related to the therapeutic use of low-dose IL-2, which belongs to their respective academic institutions and has been licensed to ILTOO Pharma. M.R. and D.K. hold shares in ILTOO Pharma. No other potential conflicts of interest relevant to this article were reported. Author Contributions. A.Y., I.S., and F.V. performed experiments. A.Y., I.S., F.V., A.P., and T.R.M. analyzed the data. M.R. and D.K. designed the clinical trial and provided patients{\textquoteright} samples. D.K. and A.P. edited the manuscript. A.P. and T.R.M. designed the study. T.R.M. wrote the manuscript. T.R.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Funding Information: This work was supported by the Diabetes Research Institute Foundation, Hollywood, FL, the Peacock Foundation, Inc., Miami, FL, the Anton E.B. Schefer Foundation, and French state funds managed by the ANR within the Investissements d'Avenir programme (ANR-11-IDEX-0004-02). Publisher Copyright: {\textcopyright} 2015 by the American Diabetes Association.",
year = "2015",
month = jun,
doi = "10.2337/db14-1322",
language = "English (US)",
volume = "64",
pages = "2172--2183",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "6",
}