Journal
BLOOD
Volume 108, Issue 5, Pages 1571-1579Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2006-02-004747
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Funding
- NHLBI NIH HHS [HL70149] Funding Source: Medline
- NIAID NIH HHS [AI29530] Funding Source: Medline
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IL-2 plays a critical role in the maintenance of CD4(+)CD25(+) FOXP3(+) regulatory T cells (Tregs) in vivo. We examined the effects of IL-2 signaling in human Tregs. In vitro, IL-2 selectively up-regulated the expression of FOXP3 in purified CD4(+)CD25(+) T cells but not in CD4(+)CD25(-) cells. This regulation involved the binding of STAT3 and STAT5 proteins to a highly conserved STAT-binding site located in the first intron of the FOXP3 gene. We also examined the effects of low-dose IL-2 treatment in 12 patients with metastatic cancer and 9 patients with chronic myelogenous leukemia after allogeneic hematopoietic stem cell transplantation. Overall, IL-2 treatment resulted in a 1.9 median fold increase in the frequency of CD4(+)CD25(+) cells in peripheral blood as well as a 9.7 median fold increase in FOXP3 expression in CD3(+) T cells. CD56(+)CD3(-) natural killer (NK) cells also expanded during IL-2 therapy but did not express FOXP3. In vitro treatment of NK cells with 5-aza-2'-deoxycytidine restored the IL-2 signaling pathway leading to FOXP3expression, suggesting that this gene was constitutively repressed by DNA methylation in these cells. Our findings support the clinical evaluation of low-dose IL-2 to selectively modulate CD4(+)CD25+ Tregs and increase expression of FOXP3in vivo.
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