Abstract
CD4+ T cells provide cell-mediated immunity in response to various antigens. During an immune response, naïve CD4+ T cells differentiate into specialized effector T helper (Th1, Th2, and Th17) cells and induced regulatory (iTreg) cells based on a cytokine milieu. In recent studies, complex phenotypes resembling more than one classical T cell lineage have been experimentally observed. Herein, we sought to characterize the capacity of T cell differentiation in response to the complex extracellular environment. We constructed a comprehensive mechanistic (logical) computational model of the signal transduction that regulates T cell differentiation. The model’s dynamics were characterized and analyzed under 511 different environmental conditions. Under these conditions, the model predicted the classical as well as the novel complex (mixed) T cell phenotypes that can co-express transcription factors (TFs) related to multiple differentiated T cell lineages. Analyses of the model suggest that the lineage decision is regulated by both compositions and dosage of signals that constitute the extracellular environment. In this regard, we first characterized the specific patterns of extracellular environments that result in novel T cell phenotypes. Next, we predicted the inputs that can regulate the transition between the canonical and complex T cell phenotypes in a dose-dependent manner. Finally, we predicted the optimal levels of inputs that can simultaneously maximize the activity of multiple lineage-specifying TFs and that can drive a phenotype toward one of the co-expressed TFs. In conclusion, our study provides new insights into the plasticity of CD4+ T cell differentiation, and also acts as a tool to design testable hypotheses for the generation of complex T cell phenotypes by various input combinations and dosages.
Highlights
The diversity and number of immunity-related diseases require a high level of heterogeneity in the immune system to maintain the overall well-being of a human
Whereas the overexpression of IL-18R resulted in a greater than twofold increase in the activity levels of GATA binding protein 3 (GATA3) and Foxp3. These results indicate that the knock-out of IL-12R favors T helper 2 (Th2) phenotype, whereas the knock-out of IL-18R favors T helper 1 (Th1) phenotype under Th1–Th2–iTreg stimulating environmental conditions
We sought to investigate the cellular phenotypes as a result of CD4+ T cell differentiation under diverse environmental conditions and understand how the balance between complex phenotypes is regulated
Summary
The diversity and number of immunity-related diseases require a high level of heterogeneity in the immune system to maintain the overall well-being of a human. A number of additional T cell subtypes, including the inducible regulatory T cells (iTregs) (Groux et al, 1997; Chen et al, 2003; Schmitt and Williams, 2013), T helper 17 (Th17) (Romagnani, 2000; Harrington et al, 2005; Mangan et al, 2006), T helper 9 (Th9) (Dardalhon et al, 2008; Veldhoen et al, 2008; Soroosh and Doherty, 2009), and follicular T helper cells (Tfh) (Breitfeld et al, 2000; Schaerli et al, 2000) have been discovered, and their functions have been extensively studied. The Th17 cells have been found to be responsible for assisting the immune response against extracellular bacteria and fungi, whereas the main role of the iTregs is to maintain the balance and regulate immune responses by the T helper cell subtypes (Zhu and Paul, 2008). The Tfh cells assist in T cell-dependent B cell response (Breitfeld et al, 2000; Schaerli et al, 2000; Ma et al, 2012)
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