PPAR γ activation drives Th17 cells into a Treg phenotype

Carbo, A., R. Hontecillas, S. Hoops, B. Kronsteiner, P. Lu, K. Wendelsdorf, Y. Mei, S. Eubank, M. Marathe, and J. Bassaganya-Riera (2012) PPAR γ activation drives Th17 cells into a Treg phenotype, American Association of Immunologists Annual Meeting, Boston MA

Th17 cells mediate inflammatory and effector responses during infectious and immune-mediated diseases. However, the mechanisms of action modulating the plasticity between Th17 and Treg are incompletely understood. To gain a better understanding of the differentiation process we have constructed a computational and mathematical model in COPASI that mimics CD4+ T cell differentiation and contemplates the plasticity between effector Th17 and Treg. Our computer simulations predicted that activation of peroxisome proliferator activated receptor gamma (PPAR) induces a switch from already differentiated Th17 into Treg. Conducted experimental validation approaches support in silico experimentation. Naive CD4+ T cells obtained from spleens of T cell-specific PPAR null, RORcGFP+/+ or wild-type donor mice, all in a C57BL6 background, were transferred to SCID and RAG2-/- recipients to induce CD4+ T cell-driven colitis. Our data demonstrate a significant decrease in the expression of FOXP3 and increase of IL-17A and RORt in recipients of PPAR null naïve CD4+ T cells when compared to recipients of naïve CD4+ T cells from wild-type mice. Furthermore, administration of PPAR agonists to recipient mice with colitis decreased the percentages of GFP+ Th17 cells at the gut mucosa. In conclusion, PPAR promotes differentiation of naïve CD4+ T cells into Treg, downregulates Th17 differentiation and favors phenotype switch from Th17 into Treg CD4+ T cells.