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Rapid and Robust Analysis of Cellular and Molecular Polarization Induced by Chemokine Signaling
Published on: December 12, 2014
Identifying Key Pathways and Components in Chemokine-Triggered T Lymphocyte Arrest Dynamics Using a Multi-Parametric
Dooyoung Lee1,2, Michael T Beste3,4, Nicholas R Anderson3
1Department of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 South 33rd St., Philadelphia, PA 19104 USA.
Introduction:
The arrest of rolling T lymphocytes at specific locations is crucial to proper immune response function. We previously developed a model of chemokine-driven integrin activation, termed integrative signaling adhesive dynamics (ISAD). In addition, we have shown that loss of diacylglycerol kinase (DGK) leads to a gain of function regarding adhesion under shear flow. We undertook this study to understand the sensitivity of adhesion to perturbations in other signaling molecules.
Methods:
We adapted multi-parametric sensitivity analysis (MPSA) for use in our ISAD model to identify important parameters, including initial protein concentrations and kinetic rate constants, for T lymphocyte arrest. We also compared MPSA results to those obtained from a single parametric sensitivity analysis.
Results:
In addition to the previously shown importance of DGK in lymphocyte arrest, PIP2 cleavage and Rap1 activation are crucial in determining T cell arrest dynamics, which agree with previous experimental findings. The l-selectin density on the T lymphocyte surface also plays a large role in determining the distance rolled before arrest. Both the MPSA and single-parametric method returned similar results regarding the most sensitive kinetic rate constants.
Conclusion:
We show here that the regulation of the amount of second messengers are, in general, more critical for determining T lymphocyte arrest over the initial signaling proteins, highlighting the importance of amplification of signaling in cell adhesion responses. Overall, this work provides a mechanistic insight of the contribution of key pathways and components, thus may help to identify potential therapeutic targets for drug development against immune disorders.
Insights
Second messenger regulation, not initial signaling proteins, is key for T lymphocyte arrest. This finding highlights signaling amplification
Area of Science:
- Immunology and Computational Biology
- Cellular Adhesion Dynamics
Background:
- T lymphocyte arrest is vital for immune response.
- Previous work established the integrative signaling adhesive dynamics (ISAD) model.
- Diacylglycerol kinase (DGK) loss enhances T cell adhesion under shear flow.
Purpose of the Study:
- To investigate the sensitivity of T lymphocyte adhesion to perturbations in signaling molecules.
- To identify critical parameters influencing T cell arrest dynamics using computational modeling.
Main Methods:
- Adapted multi-parametric sensitivity analysis (MPSA) for the ISAD model.
- Identified key parameters including protein concentrations and kinetic rate constants.
- Compared MPSA findings with single-parametric sensitivity analysis.
Main Results:
- PIP2 cleavage and Rap1 activation are critical for T cell arrest dynamics.
- L-selectin density on T cells significantly affects rolling distance before arrest.
- MPSA and single-parametric analysis yielded similar results for sensitive kinetic rate constants.
Conclusions:
- Regulation of second messenger levels is more critical than initial signaling proteins for T cell arrest.
- Signaling amplification plays a crucial role in cell adhesion responses.
- Findings offer mechanistic insights and potential therapeutic targets for immune disorders.
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