Abstract
A properly functioning immune system is vital for an organism’s wellbeing. Immune tolerance is a critical feature of the immune system that allows immune cells to mount effective responses against exogenous pathogens such as viruses and bacteria, while preventing attack to self-tissues. Activation-induced cell death (AICD) in T lymphocytes, in which repeated stimulations of the T-cell receptor (TCR) lead to activation and then apoptosis of T cells, is a major mechanism for T cell homeostasis and helps maintain peripheral immune tolerance. Defects in AICD can lead to development of autoimmune diseases. Despite its importance, the regulatory mechanisms that underlie AICD remain poorly understood, particularly at an integrative network level. Here, we develop a dynamic multi-pathway model of the integrated TCR signalling network and perform model-based analysis to characterize the network-level properties of AICD. Model simulation and analysis show that amplified activation of the transcriptional factor NFAT in response to repeated TCR stimulations, a phenomenon central to AICD, is tightly modulated by a coupled positive-negative feedback mechanism. NFAT amplification is predominantly enabled by a positive feedback self-regulated by NFAT, while opposed by a NFAT-induced negative feedback via Carabin. Furthermore, model analysis predicts an optimal therapeutic window for drugs that help minimize proliferation while maximize AICD of T cells. Overall, our study provides a comprehensive mathematical model of TCR signalling and model-based analysis offers new network-level insights into the regulation of activation-induced cell death in T cells.
Highlights
T lymphocytes are among the most abundant and versatile types of immune cells that protect human body against viral and bacterial infection[1,2]
To address if and how NFAT activation is amplified in response to weakening T-cell receptor (TCR) stimulations, we constructed a comprehensive kinetic model of the signalling network downstream of TCR and calibrated this model against experimental data
major histocompatibility complex (MHC) serves as a key model input that triggers TCR activation; while interleukin 2 (IL-2) and FasL represent major outputs of the model that drive T cell proliferation and apoptosis (AICD), respectively[33,34]
Summary
T lymphocytes (or T cells) are among the most abundant and versatile types of immune cells that protect human body against viral and bacterial infection[1,2]. While the clonal expansion of T cells is driven mainly by induction of cytokines such as interleukin 2 (IL-2)[7], the restimulation of T cells rapidly induces FasL instead[8] (Fig. 1a), both are transcriptional targets of NFAT. This raised the question as to how T cells actively suppress FasL induction during the primary stimulation to avoid cell death, but potently induce it during the secondary restimulation.
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