Date Published: January 19, 2010
Publisher: Public Library of Science
Author(s): Aya Takesono, Sarah J. Heasman, Beata Wojciak-Stothard, Ritu Garg, Anne J. Ridley, Joshua Z. Rappoport. http://doi.org/10.1371/journal.pone.0008774
Abstract: Migrating leukocytes normally have a polarized morphology with an actin-rich lamellipodium at the front and a uropod at the rear. Microtubules (MTs) are required for persistent migration and chemotaxis, but how they affect cell polarity is not known.
Partial Text: Cell migration is essential for the recruitment of T cells to and circulation within lymphoid organs, where they encounter antigen-presenting dendritic cells, and in tissues during immune surveillance, immune responses and inflammation. Migrating T cells are normally morphologically polarized with spatially distinct front (lamellipodium) and rear (uropod) structures, and migrate by extending the lamellipodium forwards and retracting the uropod –. In lymph nodes in vivo, T cells migrate rapidly and for many hours until they encounter antigen . In vitro, T cells polarize spontaneously, for example on the integrin ligand ICAM-1 , and this requires activation of the integrin LFA-1 . Similarly, neutrophils polarize and migrate in a uniform concentration of chemokine , , a process that has been termed “self-organizing polarity” , .
MT depolymerization has been shown to reduce directional migration in several cell types including human neutrophils and zebrafish macrophages , , . Here, we show that MT depolymerization converts T cells from a lamellipodial/uropod migratory phenotype to a blebbing migratory phenotype, correlating with increased RhoA/ROCK activity. ROCK inhibitors prevent blebbing and restore lamellipodial/uropod polarity to nocodazole-treated cells. In addition, we have found that ROCK inhibitors and the myosin inhibitor blebbistatin protect MTs against depolymerization. Our results support a model where RhoA/ROCK signaling contributes to T cell polarization and migration by regulating both contractility and MT stability (Figure 10).