IL-17-producing human peripheral regulatory T cells retain suppressive function.
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-1beta and IL-6, whereas IL-17 secretion was inhibited by TGFbeta. 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.
Beriou
Gaëlle
G
Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Costantino
Cristina M
CM
Ashley
Charles W
CW
Yang
Li
L
Kuchroo
Vijay K
VK
Baecher-Allan
Clare
C
Hafler
David A
DA
D015703:Antigens, CD / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006684:HLA-DR Antigens; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D016212:Transforming Growth Factor beta