CD4+ T cell differentiation studies 

Differentiation of CD4+ T cells into effector or regulatory phenotypes is tightly controlled by the cytokine milieu, complex intracellular signaling networks and numerous transcriptional regulators. We combined experimental approaches and computational modeling to investigate the mechanisms controlling differentiation and plasticity of CD4+ T cells in the gut of mice. Our computational model encompasses the major intracellular pathways involved in CD4+ T cell differentiation into T helper 1 (Th1), Th2, Th17 and induced regulatory T cells (iTreg). Sensitivity analysis predicted a critical role for peroxisome proliferator-activated receptor gamma (PPARγ) in modulating plasticity between Th17 and iTreg cells. PPARγ regulates differentiation, activation and cytokine production, thereby controlling the induction of effector and regulatory responses, and is a promising therapeutic target for dysregulated immune responses and inflammation. Our modeling efforts predict that following PPARγ activation, Th17 cells undergo phenotype switch and become iTreg cells. This prediction was validated by results of adoptive transfer studies showing an increase of colonic iTreg and a decrease of Th17 cells in the gut mucosa of mice with colitis following pharmacological activation of PPARγ. Deletion of PPARγ in CD4+ T cells impaired mucosal iTreg and enhanced colitogenic Th17 responses in mice with CD4+ T cell-induced colitis. Thus, for the first time we provide novel molecular evidence in vivo demonstrating that PPARγ in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa.

Study Overview 
Investigator: Adria Carbo, Raquel Hontecillas, Josep Bassaganya-Riera Grant: Modeling Immunity to Enteric Pathogens

Th17 cells mediate inflammatory and effector responses during infectious and immune-mediated diseases. The mechanisms of action modulating the plasticity between Th17 and Treg cells are incompletely understood. To gain a better understanding of the differentiation process we have constructed a computational 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 (PPARγ) induces a switch from already differentiated Th17 into Treg. Experimental validation approaches support this in silico prediction. The conclusion of this project is that PPARγ promotes differentiation of naïve CD4+ T cells into Treg, downregulates Th17 differentiation and favors phenotype switch from Th17 into Treg cells.

[Protocol ModCD4-PO.docx] Study Protocol Document

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