Rac activation by the T-cell receptor inhibits T cell migration.
BACKGROUND
T cell migration is essential for immune responses and inflammation. Activation of the T-cell receptor (TCR) triggers a migration stop signal to facilitate interaction with antigen-presenting cells and cell retention at inflammatory sites, but the mechanisms responsible for this effect are not known.


RESULTS
Migrating T cells are polarized with a lamellipodium at the front and uropod at the rear. Here we show that transient TCR activation induces prolonged inhibition of T-cell migration. TCR pre-activation leads to cells with multiple lamellipodia and lacking a uropod even after removal of the TCR signal. A similar phenotype is induced by expression of constitutively active Rac1, and TCR signaling activates Rac1. TCR signaling acts via Rac to reduce phosphorylation of ezrin/radixin/moesin proteins, which are required for uropod formation, and to increase stathmin phosphorylation, which regulates microtubule stability. T cell polarity and migration is partially restored by inhibiting Rac or by expressing constitutively active moesin.


CONCLUSIONS
We propose that transient TCR signaling induces sustained inhibition of T cell migration via Rac1, increased stathmin phosphorylation and reduced ERM phosphorylation which act together to inhibit T-cell migratory polarity.
Cernuda-Morollón
Eva
E
Histocompatibility and Transplantation Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.
Millán
Jaime
J
Shipman
Mark
M
Marelli-Berg
Federica M
FM
Ridley
Anne J
AJ
D000818:Animals; D002465:Cell Movement; D016764:Cell Polarity; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D050777:Stathmin / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D000099149:Ezrin
D003598:Cytoskeletal Proteins; D018799:Intercellular Adhesion Molecule-1; D008565:Membrane Proteins; D008840:Microfilament Proteins; D011948:Receptors, Antigen, T-Cell; D050777:Stathmin; D020744:rac GTP-Binding Proteins; D000099149:Ezrin; C071058:moesin; C071776:radixin
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