Submitted January 15, 2008
Accepted June 30, 2008
Human CD25highFoxp3pos regulatory T-cells differentiate into IL-17 producing cells
Hans J.P.M. Koenen*, Ruben L Smeets, Paul M Vink, Esther van Rijssen, Annemieke M.H. Boots, and Irma Joosten
Dept. of Blood transfusion and Transplantation Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
Dept. Pharmacology, NV Organon, Oss, Netherlands
* Corresponding author; email: h.koenen{at}abti.umcn.nl.
The effector T-cell lineage shows great plasticity. Th17 cells are acknowledged to be instrumental in the response against microbial infection, but are also associated with autoimmune inflammatory processes. Here, we report that human regulatory T-cells (CD4posCD25highFoxp3posCD127negCD27pos) can differentiate into IL-17 producing cells, when stimulated by allogeneic antigen presenting cells, especially monocytes, in the presence of rhIL-2/rhIL-15. These Treg derived IL-17 producing cells showed high expression of the Th17-related transcription factor ROR
t and were positively identified by CCR6 expression. This differentiation process was enhanced by exogenous IL-1
, IL-23, IL-21, while IL-6 or TGF did not affect the emergence of IL-17 producing cells. The addition of IL-1 receptor antagonist (IL-1Ra), but not anti-IL-23 antibody, reduced IL-17 producing cell numbers.
When an histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) was evaluated, we found a profound negative effect on the emergence of IL-17 producing cells from Treg, implying that Treg differentiation into IL-17 producing cells depends on histone/protein deacetylase activity. Thus, the data suggest that epigenetic modification underlies the phenomenon of Treg plasticity here described.
