The CD4+ T cell regulatory network mediates inflammatory responses during acute hyperinsulinemia: a simulation study

Abstract

Obesity is linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behavior of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood. We model how hyperinsulinemia alters the dynamics of the CD4+ T regulatory network, and this, in turn, modulates cell differentiation and plasticity. Different polarizing micro-environments are simulated under basal and high levels of insulin to assess impacts on cell-fate attainment and robustness in response to transient perturbations. In the presence of high levels of insulin Th1 and Th17 become more stable to transient perturbations and their basin sizes are augmented, IL10 producing regulatory T cells become less stable or disappear, while TGFB producing cells remain unaltered. Hence, the model provides a dynamic system-level explanation for the documented apparently paradoxical role of TGFB in both inflammation and regulation of immune responses and the emergence of the adipose Treg phenotype. Furthermore, our simulations provide novel predictions on the impact of the micro-environment in the coexistence of the different cell types, proposing that in pro-Th1, pro-Th2 and pro-Th17 environments effector and regulatory cells can coexist, but that high levels of insulin severely affect regulatory cells, specially in a pro-Th17 environment. This work provides a system-level formal and dynamic framework to integrate further experimental data in the study of complex inflammatory diseases.