Interlocked feedback loops balance the adaptive immune response

Abstract

Adaptive immune responses can be activated by harmful stimuli. Upon activation, a cascade of biochemical events ensues the proliferation and the differentiation of T cells, which can remove the stimuli and undergo cell death to maintain immune cell homeostasis. However, normal immune processes can be disrupted by certain dysregulations, leading to pathological responses, such as cytokine storms and immune escape. In this paper, a qualitative mathematical model, composed of key feedback loops within the immune system, was developed to study the dynamics of various response behaviors. First, simulation results of the model well reproduce the results of several immune response processes, particularly pathological immune responses. Next, we demonstrated how the interaction of positive and negative feedback loops leads to irreversible bistable, reversible bistable and monostable, which characterize different immune response processes: cytokine storm, normal immune response, immune escape. The stability analyses suggest that the switch-like behavior is the basis of rapid activation of the immune system, and a balance between positive and negative regulation loops is necessary to prevent pathological responses. Furthermore, we have shown how the treatment moves the system back to a healthy state from the pathological immune response. The bistable mechanism that revealed in this work is helpful to understand the dynamics of different immune response processes.