Figure 1.
Network model illustrating the complex intracellular signaling pathways and transcriptional factors controlling the CD4+ T cell differentiation process.
The signaling network illustrates network topologies associated with differentiation towards T helper (Th)1 (red shadow), Th2 (green shadow), Th17 (blue shadow) and induced regulatory T cells (iTreg, yellow shadow). The network is provided in Systems Biology Markup Language-compliant format.
Figure 2.
Activation of peroxisome proliferator-activated receptor γ (PPARγ) regulates differentiation of CD4+ T cells.
(A) Computational simulation of the effect of in silico activation of PPARγ in a T helper (Th)17 cell on the levels of FOXP3, IL-17 and RORγt. (B) PPARγ inhibits Th17 differentiation. Naïve wild-type CD4+ T cells differentiated with IL-6 in combination with TGF-β in vitro for 60h express less RORγt and produce lower levels of IL-17A when compared to T cell-specific PPARγ null Th17 cells. (C) Increasing concentrations of pioglitazone (PIO), a full PPARγ agonist, upregulate FOXP3 in wild-type Th17 differentiated cells following 24 h treatment and down-regulate RORγt and IL-17A in wild-type cells. (D) Increasing concentrations of PIO do not have an effect in PPARγ null Th17 cells. The double-positive region can be observed in the upper right part of the flow plots.
Figure 3.
Peroxisome proliferator-activated receptor (PPAR) γ suppresses T helper (Th)17 cell differentiation and upregulates FOXP3 expression in vivo.
(A–D) Computational simulation of the effect of PPARγ deficiency on differentiation from a naïve state into either Th17 or iTreg phenotypes. (E) Th17 cell accumulation in spleens of recipients of wild-type versus PPARγ null CD4+ T cells. (F) Treg cell accumulation in spleen, mesenteric lymph nodes (MLN) and lamina propria (LP) of SCID recipient mice.
Figure 4.
Peroxisome proliferator activated receptor gamma (PPARγ) ameliorates colonic inflammation and clinical signs of disease.
(A) SCID recipients were administered either wild-type or PPARγ null naïve CD4+ T cells. Representative photomicrographs of colons from (A.A–A.D) non-transferred (A.B–A.E) wild-type recipient and (A.C,A.F) T cell-specific PPARγ null recipient mice. Original magnification 40 or 100×. (B) Disease activity scores of SCID recipient mice of wild-type or PPARγ null naïve CD4+ T cells. Data are represented as mean ± standard error. Points with an asterisk are significantly different when compared to the PBS-treated group (P<0.05).
Figure 5.
Validation of the modeling prediction regarding the role of peroxisome proliferator-activated receptor (PPAR) γ in regulating the plasticity between T helper (Th) 17 and induced regulatory T cells (iTreg).
(A) Computer simulation illustrating a down-modulation of IL-17, STAT3, RORγt and upregulation of FOXP3 in a differentiated Th17 cell following PPARγ activation. (B) Combination of time-course and PPARγ concentration scan to assess changes of IL-17, STAT3, RORγt and FOXP3 over time. (C) Experimental design for the validation of the model prediction. (D–E) Accumulation of iTreg and Th17 cells in the mesenteric lymph nodes (MLN) and colonic lamina propria (LP) of recipient mice.