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Identifying Key Pathways and Components in Chemokine-Triggered T Lymphocyte Arrest Dynamics Using a Multi-Parametric Global Sensitivity Analysis

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Abstract

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.

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Abbreviations

DAG:

Diacylglycerol

DGK:

Diacylglycerol kinase

ICAM-1:

Intracellular adhesion molecule-1

ISAD:

Integrative-signaling adhesive dynamics

LFA-1:

Lymphocyte function-associated protein-1

MPSA:

Multi-parametric sensitivity analysis

GPCR:

G protein coupled receptor

IP3:

Inositol triphosphate

PIP2 :

Phosphatidylinositol 4,5-bisphosphate

PLC:

Phospholipase C

GEF:

Guanine nucleotide exchange factor

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Acknowledgments

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.

Data Availability

The codes used to perform the calculations in this paper are available upon request to the corresponding author, Daniel A. Hammer, hammer@seas.upenn.edu, in accordance with the data sharing policy of the National Institutes of Health which funded this work.

Ethical Standards

No human studies were carried out by the authors for this article. No animal studies were carried out by the authors for this article.

Author information

Author notes

  1. Dooyoung Lee

    Present address: Morphic Therapeutic, Waltham, MA, 02451, USA

  2. Michael T. Beste

    Present address: Novartis Institutes for BioMedical Research, Cambridge, MA, 02139, USA

  3. Gary A. Koretzky

    Present address: Vice Provost for Academic Integration, Cornell University, Ithaca, NY, 14850, USA

Authors and Affiliations

  1. Department of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 South 33rd St., Philadelphia, PA, 19104, USA

    Dooyoung Lee & Daniel A. Hammer

  2. Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Michael T. Beste, Nicholas R. Anderson & Daniel A. Hammer

  3. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Gary A. Koretzky

  4. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Gary A. Koretzky

  5. Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Gary A. Koretzky

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  1. Dooyoung Lee
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Contributions

DL designed the study, performed simulations, analyzed the data and wrote the paper. MTB designed the study, performed simulations and analyzed the data. NRA wrote the paper. GAK designed the study. DAH designed the study and wrote the paper.

Corresponding author

Correspondence to Daniel A. Hammer.

Additional information

Associate Editor Michael R. King oversaw the review of this article.

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Electronic Supplementary Material

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12195_2019_575_MOESM1_ESM.eps

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

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  • DOI: https://doi.org/10.1007/s12195-019-00575-2

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