Name
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-beta 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. |
Year | DOI | Venue |
|---|---|---|
2015 | 10.1371/journal.pcbi.1004324 | PLOS COMPUTATIONAL BIOLOGY |
Field | DocType | Volume |
Cell Plasticity,Transcriptional regulation,Biology,Acquired immune system,Cell type,Cellular differentiation,Signal transduction,Bioinformatics,T cell,Transcription factor | Journal | 11 |
Issue | ISSN | Citations |
6 | 1553-7358 | 4 |
PageRank | References | Authors |
0.46 | 5 | 4 |
Name | Order | Citations | PageRank |
|---|---|---|---|
| Mariana Esther Martinez-Sanchez | 1 | 4 | 0.46 |
| luis mendoza | 2 | 271 | 25.94 |
| Carlos Villarreal | 3 | 23 | 1.14 |
| Elena R Alvarez-Buylla | 4 | 62 | 5.79 |