PT - JOURNAL ARTICLE AU - Matsuoka, Ken-ichi AU - Koreth, John AU - Kim, Haesook T. AU - Bascug, Gregory AU - McDonough, Sean AU - Kawano, Yutaka AU - Murase, Kazuyuki AU - Cutler, Corey AU - Ho, Vincent T. AU - Alyea, Edwin P. AU - Armand, Philippe AU - Blazar, Bruce R. AU - Antin, Joseph H. AU - Soiffer, Robert J. AU - Ritz, Jerome TI - Low-Dose Interleukin-2 Therapy Restores Regulatory T Cell Homeostasis in Patients with Chronic Graft-Versus-Host Disease AID - 10.1126/scitranslmed.3005265 DP - 2013 Apr 03 TA - Science Translational Medicine PG - 179ra43--179ra43 VI - 5 IP - 179 4099 - http://stm.sciencemag.org/content/5/179/179ra43.short 4100 - http://stm.sciencemag.org/content/5/179/179ra43.full AB - 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.