“Playing Nice”: Transcription Factors in TH17 Cells

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Science Translational Medicine  31 Oct 2012:
Vol. 4, Issue 158, pp. 158ec198
DOI: 10.1126/scitranslmed.3005206

The immune system exists in a “love–hate” relationship with our own cells. It is responsible for maintaining our viability under the stresses of infection, autoimmune diseases, cancer, and other inflammatory disorders, yet it can also promote these same disorders when dysregulated. TH17 cells in particular play a distinct role in mucosal immune defense, cancer, and multiple autoimmune diseases. Various transcription factors (TF) are involved in the production of interleukin 17A (IL-17A), which is produced by TH17 cells, but little is known about how these TFs govern TH17 specification and cell function.

Ciofani et al. aimed to define how TH17-cell TFs work together to determine cell lineage and function. To do this, the authors used both an integrated computational and experimental approach using mouse naïve CD4+ T cells purified from lymph nodes and spleens, cultured under Th0 and TH17 conditions. An iterative systems approach combining genome-wide TF occupancy, TF mutant expression profiling, and expression time series uncovered the TH17 global transcriptional regulatory network. Ciofani and colleagues developed an accurate predictive model using multiple datasets, which was then experimentally validated in T cells. Cooperatively bound BATF and IRF4 TFs in TH17-polarized cells contributed to initial chromatin accessibility and subsequent recruitment of the nuclear receptor RORγt to regulate a selection of TH17-relevant genes. Several new TH17 regulators were identified using TF enrichment analysis, including the AP-1 family member Fosl2—a key determinant of cellular plasticity. From these data, it was clear that a collaborative series of events involving different TFs control distinct sets of genes important in TH17 cell function.

The importance of this work goes beyond the knowledge relevant to TH17 cells and related human disorders. These authors provide an example of how systems biology can be used to answer a difficult, mechanistic biological question with potential therapeutic implications. This experimental design, computational approach, and analysis framework can be tailored to other cell types, other immune system cells, and potentially specific diseases to shed light on other challenging questions. In terms of translational research, any scientific tools that can augment our understanding of the “whole” rather than the “specific” bring us closer to understanding disease sequelae in organisms, thus bringing us closer to improving human health.

M. Ciofani et al., A validated regulatory network for TH17 cell specification. Cell 151, 289–303 (2012). [Abstract]

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