Systems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticity

• DOI: 10.1371/journal.pcbi.1003027
• Publication Date: 2013-04-04T22:17:31Z
• Authors: Adria Carbo; Raquel Hontecillas; Barbara Kronsteiner; Monica Viladomiu; Mireia Pedragosa; Pinyi Lu; Casandra W. Phili...; Stefan Hoops; Madhav Marathe; Stephen Eubank; Keith Bisset; Katherine Wendels...; Abdul Jarrah; Yongguo Mei; Josep Bassaganya-...
• Keywords: Adoptive Cell Transfer

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 computational modeling to investigate mechanisms controlling differentiation plasticity in gut mice. Our model encompasses major pathways involved cell helper 1 (Th1), Th2, Th17 induced (iTreg). efforts predicted a critical role for peroxisome proliferator-activated receptor gamma (PPARγ) modulating between iTreg cells. PPARγ regulates differentiation, activation production, thereby induction responses, promising therapeutic target dysregulated immune responses inflammation. predict that following activation, undergo phenotype switch become This prediction was validated results adoptive transfer studies showing an increase colonic decrease mucosa mice with colitis pharmacological PPARγ. Deletion impaired mucosal enhanced colitogenic cell-induced colitis. Thus, first time we provide novel molecular evidence vivo demonstrating addition regulating also plays mucosa.