Article

Confinement-Optimized 3-Dimensional T cell Amoeboid Motility is Modulated via Myosin IIA-Regulated Adhesions

Department of Pathology, University of California San Francisco, San Francisco, California, USA.
Nature Immunology (Impact Factor: 20). 10/2010; 11(10):953-61. DOI: 10.1038/ni.1936
Source: PubMed

ABSTRACT

During trafficking through tissues, T cells fine-tune their motility to balance the extent and duration of cell-surface contacts versus the need to traverse an entire organ. Here we show that in vivo, myosin IIA-deficient T cells had a triad of defects, including overadherence to high-endothelial venules, less interstitial migration and inefficient completion of recirculation through lymph nodes. Spatiotemporal analysis of three-dimensional motility in microchannels showed that the degree of confinement and myosin IIA function, rather than integrin adhesion (as proposed by the haptokinetic model), optimized motility rate. This motility occurred via a myosin IIA-dependent rapid 'walking' mode with multiple small and simultaneous adhesions to the substrate, which prevented spurious and prolonged adhesions. Adhesion discrimination provided by myosin IIA is thus necessary for the optimization of motility through complex tissues.

Download full-text

Full-text

Available from: Matthieu Piel, Feb 17, 2014
    • "In addition, myosin II has an important function in accelerating migration velocity of T cells on surfaces with short wavelengths (l ¼ 20 and 40 mm; Figs. 3C and 8A), similar to the case with T cells in microchannels[38]. Therefore, overall roles of myosin II in T cell motility on highly curved surfaces seemed to be quite similar to those in microchannels. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Micro/nanofabricated surfaces have been widely used for the study of topography-guided migration of cells. While the current studies mostly utilized micro/nanostructures containing sharp edges, internal tissues guiding migration of cells such as blood and lymphatic vessels, bone cavities, perivascular tracks have smooth microscale topographical structures. To overcome these limitations, we fabricated sinusoidal wavy surfaces with various wavelengths by deep X-ray lithography enabling precise and simultaneous control of amplitudes and wavelengths. Using these surfaces, we systematically studied curvature-guided migration of T cells. The majority of T cells migrated along the concave surfaces of sinusoidal wavy structures and as wavelength increased (or curvature decreased), preference to concave surfaces decreased. Integrin-mediated adhesion augmented the tendency of T cells crawling along grooves of highly curved wavy surfaces. To understand mechanisms of curvature-guided migration of T cells, T cells were treated with small molecule drugs such as blebbistatin and CK636, inhibiting myosin II activity and lamellipodia formation, respectively. While lamellipodia-inhibited T cells frequently crossed ridges, myosin II-inhibited T cells were mostly confined within concave surfaces. These results suggest that lamellipodia regulate local actin polymerization in response to surface curvature to maintain T cells within concave surfaces while myosin II-mediated contractile forces push T cells out of concave surfaces to make T cells less sensitive to surface curvature. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · May 2015 · Biomaterials
  • Source
    • "While many cell surface ligands have been shown to be important in regulating T cell migration into lymph nodes and to inflammatory sites, relatively little is known about the intracellular signaling mechanisms that regulate migration. Recent studies have implicated signaling molecules downstream of T cell receptor signaling [11] as well as regulators of the actin cytoskeleton such as Rac GTPases and myosin IIA [12], [13], [14]. PKC proteins are important signaling mediators in many cell types including T cells, leading to changes in cellular proliferation, cytoskeleton organization, and differentiation [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cell motility is a fundamental process crucial for function in many cell types, including T cells. T cell motility is critical for T cell-mediated immune responses, including initiation, activation, and effector function. While many extracellular receptors and cytoskeletal regulators have been shown to control T cell migration, relatively few signaling mediators have been identified that can modulate T cell motility. In this study, we find a previously unknown role for PKCθ in regulating T cell migration to lymph nodes. PKCθ localizes to the migrating T cell uropod and regulates localization of the MTOC, CD43 and ERM proteins to the uropod. Furthermore, PKCθ-deficient T cells are less responsive to chemokine induced migration and are defective in migration to lymph nodes. Our results reveal a novel role for PKCθ in regulating T cell migration and demonstrate that PKCθ signals downstream of CCR7 to regulate protein localization and uropod formation.
    Full-text · Article · Nov 2013 · PLoS ONE
  • Source
    • "A growing body of work has been accumulating showing that force transmission by MyoIIA in naïve T cells is important for entry into lymph nodes during recirculation, largely shown by adoptive transfer experiments [5,15]. Intriguingly, however, using genetic ablation of MyoIIA we showed that the long-term effect of MyoIIA loss in naïve T cells is primarily to lower their interstitial motility rate and to restrict their steady-state egress from lymph nodes [5]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Following activation, T cells are released from lymph nodes to traffic via the blood to effector sites. The re-entry of these activated T cells into tissues represents a critical step for them to carry out local effector functions. Here we have assessed defects in effector T cells that are acutely depleted in Myosin-IIA (MyoIIA) and show a T cell intrinsic requirement for this motor to facilitate the diapedesis step of extravasation. We show that MyoIIA accumulates at the rear of T cells undergoing trans-endothelial migration. T cells can extend protrusions and project a substantial portion of their cytoplasm through the endothelial wall in the absence of MyoIIA. However, this motor protein plays a crucial role in allowing T cells to complete the movement of their relatively rigid nucleus through the endothelial junctions. In vivo, this defect manifests as poor entry into lymph nodes, tumors and into the spinal cord, during tissue-specific autoimmunity, but not the spleen. This suggests that therapeutic targeting of this molecule may allow for differential attenuation of tissue-specific inflammatory responses.
    Preview · Article · Sep 2013 · PLoS ONE
Show more