Bistability regulates TNFR2-mediated survival and death of T-regulatory cells

Abstract

A subgroup of T cells called T-regulatory cells (Tregs) regulates the body’s immune responses to maintain homeostasis and self-tolerance. Tregs are crucial for preventing illnesses like cancer and autoimmunity. However, contrasting patterns of Treg frequency are observed in different autoimmune diseases. The commonality of tumour necrosis factor receptor 2 (TNFR2) defects and decrease in Treg frequency on the onset of autoimmunity demands an in-depth study of the TNFR2 pathway. To unravel this mystery, we need to study the mechanism of cell survival and death in Tregs. Here, we construct an ordinary differential equation (ODE)-based model to capture the mechanism of cell survival and apoptosis in Treg cells via TNFR2 signalling. The sensitivity analysis reveals that the input stimulus, the concentration of tumour necrosis factor (TNF), is the most sensitive parameter for the model system. The model shows that the cell goes into survival or apoptosis via bistable switching. Through hysteretic switching, the system tries to cope with the changing stimuli. In order to understand how stimulus strength and feedback strength influence cell survival and death, we compute bifurcation diagrams and obtain cell fate maps. Our results indicate that the elevated TNF concentration and increased c-Jun N-terminal kinase (JNK) phosphorylation are the major contributors to the death of T-regulatory cells. Biological evidence cements our hypothesis and can be controlled by reducing the TNF concentration. Finally, the system was studied under stochastic perturbation to see the effect of noise on the system’s dynamics. We observed that introducing random perturbations disrupts the bistability, reducing the system’s bistable region, which can affect the system’s normal functioning.