(A) system-level investigation into nuclear factor of activated T-cells signal amplification and activation induced cell death in T-lymphocyte: a mathematical modeling approach

Abstract

Clonal expansion of antigen-reactive T cells followed by rapid induction of apoptosis in a process known as activation-induced cell death (AICD) has been characterized as a fundamental mechanism to maintain immune homeostasis. Yet, the underlying mechanism of how sequential stimulations of TCR switch T cells from proliferative to apoptotic during AICD is not fully understood. Apoptosis of T cells during AICD is primarily caused by induction of the death ligand FasL, which is directly transcribed by the transcriptional factor NFAT following TCR activation. This raises the question as to how NFAT activity is kept minimal during the clonal expansion phase but amplified during the apoptosis phase (to induce FasL), given that the primary TCR stimulation is paradoxically considered stronger than the secondary one. We hypothesize that this counter-intuitive feature is an emergent property of the integrative TCR/Calcineurin/NFAT-IL2/FasL signaling-transcriptional network. Here, we construct the first detailed, mathematical model of this network and calibrated it using experimental data from T cells and revealed that the seemingly paradoxical phenomenon regarding NFAT amplification can be robustly achieved by the network. Model simulations revealed the coupled feedback mechanisms in controlling NFAT amplification and that depending on their strength, these feedback loops can switch role from promoting to inhibiting the amplification of NFAT activity. Interestingly, model-based analysis revealed an optimal therapeutic window for the immunosupressant Cyclosporin A (CsA), within this range it maximizes its drug effect by minimizing the proliferation while maximizing AICD of T cells, providing novel insights into the mechanism underlying the therapeutic effects of CsA. In summary, our modelling and systems analysis approach shed new lights on the activation-induced cell death of T cells at a systems level and propose new potential therapeutic strategy for immune suppression.