Journal
BLOOD
Volume 113, Issue 18, Pages 4240-4249Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-10-183251
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Funding
- National Multiple Sclerosis Society [FG1744A1, RG3825A1]
- National Institutes of Health [U19AI070352, R01NS024247, P01AI03971, P01NS038037]
- National Institute of Neurological Disorders and Stroke
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Although implicated in antagonistic functions, both regulatory T cells (Tregs) and Th17 effector cells play an important role in controlling autoimmune pathogenesis. Paradoxically, recent studies indicate that Tregs have the capacity to produce interleukin-17 (IL-17), although the ability of these cells to retain their suppressive function remains unknown. Here we report that human Tregs within the CD4(+) CD45RA(-) CD25(high)CCR6(+) HLA-DR(-)FoxP3(+) population produce IL-17 when activated in the presence of the proinflammatory cytokines IL-1 beta and IL-6, whereas IL-17 secretion was inhibited by TGF beta. To assess the ability of a single Treg to secrete IL-17 and to suppress in vitro immune function, we isolated clones from this population. We found that IL-17(+)/FoxP3(+) Treg clones retain suppressive function and exhibit the plasticity to secrete IL-17 or suppress depending on the nature of the stimulus provided. IL-17 production by these Treg clones was accompanied by sustained FoxP3 expression and concomitant, but reversible, loss of suppressive activity. Our data demonstrate that at the single cell level a subset of in vitro suppressive FoxP3(+) cells can be driven to secrete IL-17 under inflammatory conditions. These findings suggest a new mechanism by which inflammation can drive Tregs to secrete IL-17, thereby dampening suppression and promoting an inflammatory milieu. ( Blood. 2009;113:4240-4249)
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