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Bioinformatics, Computational and Systems Biology

Bioinformatics, Computational and Systems Biology - Poster Session E

N10 - Systems Model Predicts Switch-like Behavior of IL-2 Production in CD4+ T-Cells

Saturday, October 11, 2025
10:00 AM - 11:00 AM PDT
Location: Exhibit Hall F, G & H

Introduction: : Heart failure (HF) is a national issue impacting 6.7 million people across the country and estimated to increase to over 8 million people impacted by 2030(1). T-cell activation plays an important role in controlling the wound healing response to heart injury; however, excessive activation of T-cells drives pathological cardiac inflammation and fibrosis, ultimately resulting in HF(2). Activated CD4+ Th1 cells drive cardiac fibrosis and dysfunction in pressure overload mouse models of non-ischemic HF(3). While prior studies have elucidated individual protein interactions in T-cells, a computational model for T-cells is needed to capture the entire signaling network in CD4 T-cells . To identify drivers of CD4 T-cell activation, we built an intracellular network model for CD4 T-cell activation .

Materials and

Methods: : A logic-based ordinary di fferential equation model of CD4+ T-cell activation was built in Netflux using experimental data from primary research articles. Model outputs were compared against experimental results from independent studies to validate predictions. Species activity was measured as a function of MHCII input signal strength. Change in species activity was plotted against input signal strength to identify trends. IL2 activity vs MHCII signal strength was fit to a Hill equation to quantify switch-like behavior and identify EC50 value.

Results, Conclusions, and Discussions:: A model of CD4+ T-cell activation was created with 29 nodes and 32 reactions (Figure 1). 31 of 40 (77.5%) in vitro experimental results from Jurkat T cells matched model predictions. Measuring species activity in relation to MHCII signal strength revealed key species for T-cell activation like IL2, PLCg1, NFAT, and NFkB undergo significant changes in activation levels with small changes in MHCII signaling (Figure 2A). Fitting the dose response curve of IL2 against MHCII signal identified a Hill coefficient of 13.64 with an EC50 value of 0.79 (Figure 2B). A large Hill coefficient signifies an ultra-sensitive response of IL2 and EC50 value indicates a need for high MHCII signal strength to activate.
In this study we built an intracellular model of CD4+ T-cell activation to better understand mechanisms driving CD4+ TCR activation. We show that IL2 exhibits an ultra-sensitive response to MHCII interactions from the antigen presenting cell, indicating that IL2 production leading to T-cell activation exhibits switch like behavior and that CD4+ T-cells begin activation under strong levels of MHCII presentation . Signaling motifs in the model such as feed-forward loops may play a role in IL2 ultra sensitivity. Future work includes adding T-cell survival and differentiation pathways to the model, exploring mechanisms that drive the ultra-sensitive response of T-cells, and in vitro experiments testing network mechanisms .

Acknowledgements and/or References (Optional): : Acknowledgments: Funding Sources – NSF Award #2447802

References: 1. Martin, S. S., et al, Circulation Research, 2024 2. Travers, J. G., et al, Circulation Research, 2016 3. Nevers, T., et al, The Journal of experimental medicine, 2017