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

Aixin Yu, Isaac Snowhite, Francesco Vendrame, Michelle Rosenzwajg, David Klatzmann, Alberto Pugliese, Thomas R. Malek

Research output: Contribution to journalArticle

84 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2172-2183
Number of pages12
JournalDiabetes
Volume64
Issue number6
DOIs
StatePublished - Jun 2015

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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