title: A Mathematical Framework for Understanding Four-Dimensional Heterogeneous Differentiation of CD4+ T Cells.
abstract: At least four distinct lineages of CD4+ T cells play diverse roles in the immune system. Both in vivo and in vitro, naïve CD4+ T cells often differentiate into a variety of cellular phenotypes. Previously, we developed a mathematical framework to study heterogeneous differentiation of two lineages governed by a mutual-inhibition motif. To understand heterogeneous differentiation of CD4+ T cells involving more than two lineages, we present here a mathematical framework for the analysis of multiple stable steady states in dynamical systems with multiple state variables interacting through multiple mutual-inhibition loops. A mathematical model for CD4+ T cells based on this framework can reproduce known properties of heterogeneous differentiation involving multiple lineages of this cell differentiation system, such as heterogeneous differentiation of TH1-TH2, TH1-TH17 and iTReg-TH17 under single or mixed types of differentiation stimuli. The model shows that high concentrations of differentiation stimuli favor the formation of phenotypes with co-expression of lineage-specific master regulators.
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Hong
authors.forename: Cihan
authors.initials: C
authors.lastname: Oguz
authors.forename: John J
authors.initials: JJ
authors.lastname: Tyson
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D003198:Computer Simulation; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D055641:Mathematical Concepts; D018448:Models, Immunological
chemical_list: D016207:Cytokines