Abstract
T lymphocytes utilize amoeboid migration to navigate effectively within complex microenvironments. The precise rearrangement of the actin cytoskeleton required for cellular forward propulsion is mediated by actin regulators, including the actin‐related protein 2/3 (Arp2/3) complex, a macromolecular machine that nucleates branched actin filaments at the leading edge. The consequences of modulating Arp2/3 activity on the biophysical properties of the actomyosin cortex and downstream T cell function are incompletely understood. We report that even a moderate decrease of Arp3 levels in T cells profoundly affects actin cortex integrity. Reduction in total F‐actin content leads to reduced cortical tension and disrupted lamellipodia formation. Instead, in Arp3‐knockdown cells, the motility mode is dominated by blebbing migration characterized by transient, balloon‐like protrusions at the leading edge. Although this migration mode seems to be compatible with interstitial migration in three‐dimensional environments, diminished locomotion kinetics and impaired cytotoxicity interfere with optimal T cell function. These findings define the importance of finely tuned, Arp2/3‐dependent mechanophysical membrane integrity in cytotoxic effector T lymphocyte activities.
Highlights
Cytotoxic effector T lymphocytes (CTLs) provide immunosurveillance against invading pathogens and malignant cells.[1,2] To effectively contribute to successful immune responses, CTLs employ flexible migratory programs that are informed by extrinsic and intrinsic factors.[3,4,5] migrating CTLs in situ adopt a polarized cell shape defined by the formation of a lamellipodium at the leading edge and a uropod at the rear of the cell.[6]
Cells isolated from OT-I T cell receptor (TCR) transgenic mice in which the CD8+ T cells express a TCR specific for the SIINFEKL peptide of ovalbumin presented on kb
Mice were crossed to either recombination activating-gene 1 (Rag1–/–) background or enhanced green fluorescent protein (EGFP)-Lifeact mice, in which EGFP is fused to the F-actin-binding peptide, Lifeact.[38]
Summary
Cytotoxic effector T lymphocytes (CTLs) provide immunosurveillance against invading pathogens and malignant cells.[1,2] To effectively contribute to successful immune responses, CTLs employ flexible migratory programs that are informed by extrinsic (e.g. chemokines, stromal elements) and intrinsic (signaling molecules, cytoskeleton) factors.[3,4,5] migrating CTLs in situ adopt a polarized cell shape defined by the formation of a lamellipodium at the leading edge and a uropod at the rear of the cell.[6]. The structure and function of the actomyosin cortex is highly cell-type dependent and governed by the submembranous cytoskeleton, which comprises actin network filaments, actin-binding proteins and myosin-II.[9]. Together, these actin regulators control the cell shape changes requisite for cell migration through the interstitial spaces of organs. Lamellipodia motility seems to allow precise sensing of the microenvironment and might provide navigation guidance based on the rigidity of the substrate measured via formation of focal adhesions.[36] These require precise regulation of actin polymerization and dendritic network growth and matrix proteolysis. While many key issues still need to be addressed, our study provides a model system for studying the molecular and physiological aspects of blebbing migration
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