An IL-2 Paradox: Blocking CD25 on T Cells Induces IL-2–Driven Activation of CD56bright NK Cells
Open Access
- 15 July 2010
- journal article
- Published by The American Association of Immunologists
- Vol. 185 (2), 1311-1320
- https://doi.org/10.4049/jimmunol.0902238
Abstract
Daclizumab (Dac), an Ab against the IL-2R α-chain, inhibits brain inflammation in patients with multiple sclerosis, while expanding CD56bright immunoregulatory NK cells in vivo. We hypothesized that this unexpected expansion is paradoxically IL-2 driven; caused by the increased availability of T cell-derived IL-2 for NK cell signaling. To this end, we performed ex vivo functional analyses of CD56bright NK cells and T cells from patients in clinical trials with Dac. We developed in vitro models to investigate mechanisms for ex vivo observations. We observed that Dac treatment caused decreased numbers and proliferation of FoxP3+ T regulatory cells (Tregs), a model T cell population known to be dependent on IL-2 for proliferation and survival. As anticipated, Dac therapy inhibited IL-2 signaling in all T cells; however, we also observed functional adaptation of T cells to low IL-2 signal in vivo, characterized by the concomitant enhancement of IL-7 signaling on all T cells and parallel increase of CD127 expression by Tregs. In contrast, IL-2 signaling on CD56bright NK cells was not inhibited by Dac and their in vivo proliferation and cytotoxicity actually increased. Mechanistic studies indicated that the activation of CD56bright NK cells was likely IL-2 driven, as low doses of IL-2, but not IL-15, mimicked this activation in vitro. Our study provides insight into the role that IL-2 and CD25 play in functional regulation of two important immunoregulatory cell populations in humans: FoxP3+ Tregs and CD56bright NK cells.Keywords
This publication has 31 references indexed in Scilit:
- Effect of Anti-CD25 Antibody Daclizumab in the Inhibition of Inflammation and Stabilization of Disease Progression in Multiple SclerosisArchives of Neurology, 2009
- Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon βProceedings of the National Academy of Sciences of the United States of America, 2004
- Clinical relapses of multiple sclerosis are associated with ‘novel’ valleys in natural killer cell functional activityJournal of Neuroimmunology, 2003
- The natural killer cell‐mediated killing of autologous dendritic cells is confined to a cell subset expressing CD94/NKG2A, but lacking inhibitory killer Ig‐like receptorsEuropean Journal of Immunology, 2003
- IL-2 negatively regulates IL-7 receptor α chain expression in activated T lymphocytesProceedings of the National Academy of Sciences of the United States of America, 2002
- The IL-2/IL-15 Receptor Systems: Targets for ImmunotherapyJournal of Clinical Immunology, 2002
- Potential mechanisms of human natural killer cell expansion in vivo during low-dose IL-2 therapyJCI Insight, 2000
- Treatment of noninfectious intermediate and posterior uveitis with the humanized anti-Tac mAb: A phase I/II clinical trialProceedings of the National Academy of Sciences, 1999
- Regulation of Experimental Autoimmune Encephalomyelitis by Natural Killer (NK) CellsThe Journal of Experimental Medicine, 1997
- DYSFUNCTION OF NATURAL-KILLER CELLS IN MULTIPLE-SCLEROSIS - A POSSIBLE PATHOGENETIC FACTOR1980