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LFA-1 signals to promote actin polymerization and upstream migration in T cells

Nathan H Roy, Sarah Hyun Ji Kim, Alexander Buffone Jr, Daniel Blumenthal, Bonnie Huang, Sangya Agarwal, Pamela L Schwartzberg, Daniel A Hammer, View ORCID ProfileJanis K Burkhardt
doi: https://doi.org/10.1101/2020.04.29.069302
Nathan H Roy
1Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA, USA
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Sarah Hyun Ji Kim
4Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA, USA
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Alexander Buffone Jr
3Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
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Daniel Blumenthal
1Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA, USA
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Bonnie Huang
5Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
6National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
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Sangya Agarwal
2Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Pamela L Schwartzberg
5Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
6National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
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Daniel A Hammer
3Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
4Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA, USA
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Janis K Burkhardt
1Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA, USA
2Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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  • ORCID record for Janis K Burkhardt
  • For correspondence: jburkhar@pennmedicine.upenn.edu
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Abstract

T cell entry into inflamed tissue requires firm adhesion, cell spreading, and migration along and through the endothelial wall. These events require the T cell integrins LFA-1 and VLA-4 and their endothelial ligands ICAM-1 and VCAM-1, respectively. T cells migrate against the direction of shear flow on ICAM-1 and with the direction of shear flow on VCAM-1, suggesting that these two ligands trigger distinct cellular responses. However, the contribution of specific signaling events downstream of LFA-1 and VLA-4 has not been explored. Using primary mouse T cells, we found that engagement of LFA-1, but not VLA-4, induces cell shape changes associated with rapid 2D migration. Moreover, LFA-1 ligation results in activation of the PI3K and ERK pathways, and phosphorylation of multiple kinases and adaptor proteins, while VLA-4 ligation triggers only a subset of these signaling events. Importantly, T cells lacking Crk adaptor proteins, key LFA-1 signaling intermediates, or the ubiquitin ligase cCbl, failed to migrate against the direction of shear flow on ICAM-1. These studies identify novel signaling differences downstream of LFA-1 and VLA-4 that drive T cell migratory behavior.

Summary Statement Inflammatory responses require leukocyte migration along the vascular wall. We show that signaling from β2, but not β1, integrins induces cytoskeletal changes needed for upstream migration under shear flow.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 02, 2020.
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LFA-1 signals to promote actin polymerization and upstream migration in T cells
Nathan H Roy, Sarah Hyun Ji Kim, Alexander Buffone Jr, Daniel Blumenthal, Bonnie Huang, Sangya Agarwal, Pamela L Schwartzberg, Daniel A Hammer, Janis K Burkhardt
bioRxiv 2020.04.29.069302; doi: https://doi.org/10.1101/2020.04.29.069302
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LFA-1 signals to promote actin polymerization and upstream migration in T cells
Nathan H Roy, Sarah Hyun Ji Kim, Alexander Buffone Jr, Daniel Blumenthal, Bonnie Huang, Sangya Agarwal, Pamela L Schwartzberg, Daniel A Hammer, Janis K Burkhardt
bioRxiv 2020.04.29.069302; doi: https://doi.org/10.1101/2020.04.29.069302

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