Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease

Ken-ichi Matsuoka, John Koreth, Haesook T. Kim, Gregory Bascug, Sean McDonough, Yutaka Kawano, Kazuyuki Murase, Corey Cutler, Vincent T. Ho, Edwin P. Alyea, Philippe Armand, Bruce R. Blazar, Joseph H. Antin, Robert J. Soiffer, Jerome Ritz

Research output: Contribution to journalArticle

235 Citations (Scopus)

Abstract

CD4+Foxp3+ regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation. We recently reported that daily administration of low-dose interleukin-2 (IL-2) induces selective expansion of functional Tregs and clinical improvement of chronic graft-versus-host disease (GVHD). To define the mechanisms of action of IL-2 therapy, we examined the immunologic effects of this treatment on homeostasis of CD4+ T cell subsets after transplant. We first demonstrated that chronic GVHD is characterized by constitutive phosphorylation of signal transducer and activator of transcription 5 (Stat5) in conventional CD4 + T cells (Tcons) associated with elevated amounts of IL-7 and IL-15 and relative functional deficiency of IL-2. IL-2 therapy resulted in the selective increase of Stat5 phosphorylation in Tregs and a decrease of phosphorylated Stat5 in Tcons. Over an 8-week period, IL-2 therapy induced a series of changes in Treg homeostasis, including increased proliferation, increased thymic export, and enhanced resistance to apoptosis. Low-dose IL-2 had minimal effects on Tcons. These findings define the mechanisms whereby low-dose IL-2 therapy restores the homeostasis of CD4+ T cell subsets and promotes the reestablishment of immune tolerance.

Original languageEnglish
Article number179ra43
JournalScience Translational Medicine
Volume5
Issue number179
DOIs
Publication statusPublished - Apr 3 2013
Externally publishedYes

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Graft vs Host Disease
Regulatory T-Lymphocytes
Interleukin-2
Homeostasis
STAT5 Transcription Factor
Immune Tolerance
T-Lymphocyte Subsets
Therapeutics
Phosphorylation
Interleukin-15
Interleukin-7
Hematopoietic Stem Cell Transplantation
Maintenance
Apoptosis
T-Lymphocytes
Transplants

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. / Matsuoka, Ken-ichi; Koreth, John; Kim, Haesook T.; Bascug, Gregory; McDonough, Sean; Kawano, Yutaka; Murase, Kazuyuki; Cutler, Corey; Ho, Vincent T.; Alyea, Edwin P.; Armand, Philippe; Blazar, Bruce R.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jerome.

In: Science Translational Medicine, Vol. 5, No. 179, 179ra43, 03.04.2013.

Research output: Contribution to journalArticle

Matsuoka, K, Koreth, J, Kim, HT, Bascug, G, McDonough, S, Kawano, Y, Murase, K, Cutler, C, Ho, VT, Alyea, EP, Armand, P, Blazar, BR, Antin, JH, Soiffer, RJ & Ritz, J 2013, 'Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease', Science Translational Medicine, vol. 5, no. 179, 179ra43. https://doi.org/10.1126/scitranslmed.3005265
Matsuoka, Ken-ichi ; Koreth, John ; Kim, Haesook T. ; Bascug, Gregory ; McDonough, Sean ; Kawano, Yutaka ; Murase, Kazuyuki ; Cutler, Corey ; Ho, Vincent T. ; Alyea, Edwin P. ; Armand, Philippe ; Blazar, Bruce R. ; Antin, Joseph H. ; Soiffer, Robert J. ; Ritz, Jerome. / Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. In: Science Translational Medicine. 2013 ; Vol. 5, No. 179.
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