Low-Dose Interleukin-2 Therapy Restores Regulatory T Cell Homeostasis in Patients with Chronic Graft-Versus-Host Disease

Regulatory T cell homeostasis is restored in patients with chronic graft-versus-host disease who receive low-dose interleukin-2 therapy. Restoring Balance to the Immune System Hematopoietic stem cell transplantation can be a lifesaving therapy for patients with certain types of cancers or other blood disorders. However, it’s rare to find a perfect match, and transplants frequently occur from donors who are antigenically different from the recipient. When this happens, the graft itself can attack the host as foreign tissue, a response called graft-versus-host disease (GVHD). Matsuoka et al. now report that daily low-dose interleukin-2 (IL-2) can expand regulatory T cells (Tregs) and improve chronic GVHD. The authors studied the effects of daily low-dose IL-2 on different subsets of CD4+ T cells in patients with chronic GVHD. Conventional T cells in these patients had altered phosphorylation of the signaling molecule signal transducer and activator of transcription 5 (Stat5) and a functional deficiency in IL-2. When this IL-2 deficiency was replaced with their therapy, Stat5 phosphorylation levels were selectively increased in Tregs but decreased conventional T cells. Indeed, although daily low-dose IL-2 had minimal effects on conventional T cells, it induced a series of changes to Treg homeostasis that likely led to the establishment of immune tolerance. 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.