Role of Arp2/3 in blebbing migration of T lymphocytes in vivo

Obeidy P1, Ju L2, Oehlers S1, Zulkhernain NS1, Galeano Nino LG3, Tikoo S1, Jackson SP2, Biro M3, Roediger B1 and Weninger W1

  1. The Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW 2042, Australia.
  2. Heart Research Institute, Charles Perkins Centre, University of Sydney, Camperdown, NSW 2006, Australia.
  3. Cell Motility and Mechanobiology, School of Medical Sciences, University of New South Wales, Sydney, 2050 NSW, Australia.

Cytotoxic T lymphocytes (CTL) rely on the precise rearrangement of the actin cytoskeleton to provide immunosurveillance against invading pathogens and malignant cells. Constant remodelling of the cytoskeleton, particularly at the leading edge, is associated with efficient T cell migration and function. The consequences of modulating Arp2/3, a macromolecular machine that nucleates branched actin filaments, at the leading edge of migrating T cells are incompletely understood. We report that modulation of Arp3 (one of the main subunits of Arp2/3) profoundly affects CTL actin cortex integrity, surveillance in vivo and effector function in vitro. We also demonstrate a significant reduction in the total F-actin resulting in decreased cortical tension and disruption of lamellipodia formation. As a result, Arp3 knockdown CTL switched from lamellipodia-based migration to the blebbing mode characterised by transient, membrane balloon-like protrusions at the leading edge both in vitro and in a zebrafish model. Our study established that optimal mechano-physical and biochemical properties of the actomyosin cortex, as maintained by the Arp2/3 complex, are essential for the proper functioning and effective migration of CTL. These unforeseen findings pave the way for a deeper understanding of actin nucleators in T cell cytoskeleton and are crucial for the development of improved therapies for cancer and inflammatory diseases.