The Roles of Actin and Microtubule-based Motor Proteins in T Cell Activation Public Deposited

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  • March 22, 2019
  • Yi, Chang K.
    • Affiliation: College of Arts and Sciences, Department of Biology
  • T cell activation is a critical process in our body's fight against infection and disease. The activation process begins upon encounter with stimulatory antigen presenting cells (APCs), which leads to the rapid polarization of various cellular components in T cells. At the membrane of the contact site, T cell receptors (TCRs), adhesion molecules, and other accessory components become differentially clustered and rearranged to form a supra-molecular structure called the immunological synapse. While both actin retrograde flow and myosin IIA activity have been implicated in immunological synapse formation, their relative organization and dynamics at the immunological synapse, and their relative contributions toward the reorganization of receptor clusters have not been fully understood. In this study, we show that the immunological synapse is essentially a radially symmetric migrating cell, as previously hypothesized, and provide direct proof that classical lamellipodial and lamellar actin networks localize at dSMAC and pSMAC regions, respectively. Moreover, our experiments using actin and myosin II inhibitors reveal that actin retrograde flow and actomyosin II contraction work coordinately to drive the inward movements of receptor clusters at the immunological synapse. Concomitant with immunological synapse formation, the microtubule organizing center (MTOC) polarizes rapidly toward the contact site with the APC to position the secretory apparatus for directed secretion. Due to the lack of spatial and temporal control in most previous studies, the kinetics of MTOC repositioning have not been well characterized in T cells. In addition, the specific roles of dynein and dynein regulatory proteins during T cell activation have not been defined. In this study, we show using an optical trap-controlled T cell activation method that TCR and LFA-1 signaling are both required for robust MTOC repositioning. Moreover, we report that the repositioning process is bi-phasic, with distinct kinetics at each phase of MTOC movement. Lastly, inhibition experiments using dominant negative constructs show that dynein and LIS1 are required for both phases of MTOC repositioning. In conclusion, the actin and microtubule cytoskeletal systems mediate many distinct aspects of T cell activation, and are critical components of the overall adaptive immune response.
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  • In Copyright
  • Hammer, John A.
  • Doctor of Philosophy
Graduation year
  • 2012

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