title: A Minimal Regulatory Network of Extrinsic and Intrinsic Factors Recovers Observed Patterns of CD4+ T Cell Differentiation and Plasticity.
abstract: CD4+ T cells orchestrate the adaptive immune response in vertebrates. While both experimental and modeling work has been conducted to understand the molecular genetic mechanisms involved in CD4+ T cell responses and fate attainment, the dynamic role of intrinsic (produced by CD4+ T lymphocytes) versus extrinsic (produced by other cells) components remains unclear, and the mechanistic and dynamic understanding of the plastic responses of these cells remains incomplete. In this work, we studied a regulatory network for the core transcription factors involved in CD4+ T cell-fate attainment. We first show that this core is not sufficient to recover common CD4+ T phenotypes. We thus postulate a minimal Boolean regulatory network model derived from a larger and more comprehensive network that is based on experimental data. The minimal network integrates transcriptional regulation, signaling pathways and the micro-environment. This network model recovers reported configurations of most of the characterized cell types (Th0, Th1, Th2, Th17, Tfh, Th9, iTreg, and Foxp3-independent T regulatory cells). This transcriptional-signaling regulatory network is robust and recovers mutant configurations that have been reported experimentally. Additionally, this model recovers many of the plasticity patterns documented for different T CD4+ cell types, as summarized in a cell-fate map. We tested the effects of various micro-environments and transient perturbations on such transitions among CD4+ T cell types. Interestingly, most cell-fate transitions were induced by transient activations, with the opposite behavior associated with transient inhibitions. Finally, we used a novel methodology was used to establish that T-bet, TGF-β and suppressors of cytokine signaling proteins are keys to recovering observed CD4+ T cell plastic responses. In conclusion, the observed CD4+ T cell-types and transition patterns emerge from the feedback between the intrinsic or intracellular regulatory core and the micro-environment. We discuss the broader use of this approach for other plastic systems and possible therapeutic interventions.
authors.affiliation: Departamento de Ecología Funcional, Instituto de Ecología, Universidad Nacional Autónoma de México, Coyoacán, México Distrito Federal, México; Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Coyoacán, México Distrito Federal, México.
authors.forename: Mariana Esther
authors.initials: ME
authors.lastname: Martinez-Sanchez
authors.affiliation: Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México Distrito Federal, México.
authors.forename: Luis
authors.initials: L
authors.lastname: Mendoza
authors.affiliation: Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Coyoacán, México Distrito Federal, México; Departamento de Física Teórica, Instituto de Física, Universidad Nacional Autónoma de México, México Distrito Federal, México.
authors.forename: Carlos
authors.initials: C
authors.lastname: Villarreal
authors.affiliation: Departamento de Ecología Funcional, Instituto de Ecología, Universidad Nacional Autónoma de México, Coyoacán, México Distrito Federal, México; Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Coyoacán, México Distrito Federal, México.
authors.forename: Elena R
authors.initials: ER
authors.lastname: Alvarez-Buylla
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D000066670:Cell Plasticity / Q000276:immunology*; D060833:Cellular Microenvironment; D019295:Computational Biology; D016207:Cytokines / Q000378:metabolism; D018448:Models, Immunological; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D016207:Cytokines