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

Nathan H. Roy, Sarah Hyun Ji Kim, Alexander Buffone, Daniel Blumenthal, Bonnie Huang, Sangya Agarwal, Pamela L. Schwartzberg, Daniel A. Hammer, Janis K. Burkhardt

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 phosphoinositide 3-kinase (PI3K) and ERK pathways, and phosphorylation of multiple kinases and adaptor proteins, whereas 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 (also known as CBL), 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.

Original languageEnglish (US)
Article numberjcs248328
JournalJournal of Cell Science
Volume133
Issue number17
DOIs
StatePublished - Sep 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cell Biology

Keywords

  • Actin
  • Integrins
  • Migration
  • Shear flow
  • Signaling
  • T cell

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