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.
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.
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.
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.
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Intracellular adhesion molecule-1
Integrative-signaling adhesive dynamics
Lymphocyte function-associated protein-1
Multi-parametric sensitivity analysis
G protein coupled receptor
- PIP2 :
Guanine nucleotide exchange factor
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This work was supported by NIH 1R01AI082292 (D.A.H. and G.A.K.) and 5R01GM123019 (D.A.H.).
Conflict of interest
Dooyoung Lee, Michael T. Beste, Nicholas R. Anderson, Gary A. Koretzky and Daniel A. Hammer declare that they have no conflicts of interest.
The codes used to perform the calculations in this paper are available upon request to the corresponding author, Daniel A. Hammer, firstname.lastname@example.org, in accordance with the data sharing policy of the National Institutes of Health which funded this work.
No human studies were carried out by the authors for this article. No animal studies were carried out by the authors for this article.
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Electronic Supplementary Material
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Supplemental Fig. 1. Cumulative frequency of MPSA with respect to kinetic parameters in chemokine-triggered integrin LFA-1 activation signaling during T lymphocyte trafficking under flow using distance to stop as metric of interest. Red curves represent unacceptable cases and blue curves denote acceptable cases. The K–S statistic is calculated with the maximal vertical difference between the two curves.. Supplementary material 1 (EPS 1570 kb)
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Lee, D., Beste, M.T., Anderson, N.R. et al. Identifying Key Pathways and Components in Chemokine-Triggered T Lymphocyte Arrest Dynamics Using a Multi-Parametric Global Sensitivity Analysis. Cel. Mol. Bioeng. 12, 193–202 (2019). https://doi.org/10.1007/s12195-019-00575-2
- Sensitivity analysis
- T lymphocyte
- Firm arrest