Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 5, Issue 179, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3005265
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Funding
- NIH [AI29530, CA142106]
- Jock and Bunny Adams Research and Education Endowment
- Ted and Eileen Pasquarello Research Fund
- Dana-Farber Dunkin' Donuts Rising Star award
- American Society of Blood and Marrow Transplantation/Pharmion New Investigator award
- Grants-in-Aid for Scientific Research [24790975] Funding Source: KAKEN
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CD4(+)Foxp3(+) regulatory T cells (T-regs) 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 T-regs 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 (T-cons) 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 T-regs and a decrease of phosphorylated Stat5 in T-cons. Over an 8-week period, IL-2 therapy induced a series of changes in T-reg homeostasis, including increased proliferation, increased thymic export, and enhanced resistance to apoptosis. Low-dose IL-2 had minimal effects on T-cons. 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.
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