Interfacial actin protrusions mechanically potentiate killing by cytotoxic T cells

Tamzalit, Fella; Wang, Mitchell S.; Jin, Weiyang; Boyko, Vitaly; Heddleston, John M.; Black, Charles T.; Kam, Lance C.; Huse, Morgan

doi:10.1101/443309

Cited by 2 publications

(1 citation statement)

References 63 publications

(86 reference statements)

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“…Together, the data presented in this report highlights a novel molecular mechanism in modulating early TCR signaling, CD8+ T cell activation, and cytotoxic function as target cell stiffness changes. This is distinct from a previous study that implied the role of WASP in generating actin protrusions and forces at the level of target killing 61 . We show that WASP is crucial in both sensing as well as generating the forces at the synapse and is crucial for the early stages of T cell activation itself before the cytotoxicity step would be initiated.…”

Section: Discussioncontrasting

confidence: 99%

WASP facilitates tumor mechanosensitivity in T lymphocytes

Mandal,

Melo,

Gordiichuk

et al. 2023

Preprint

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Cytotoxic T lymphocytes (CTLs) carry out immunosurveillance by scanning target cells of diverse physical properties for the presence of antigens. While the recognition of cognate antigen by the T cell receptor is the primary signal for CTL activation, it has become increasingly clear that the mechanical stiffness of target cells plays an important role in antigen-triggered T cell responses. However, the molecular machinery within CTLs that transduces the mechanical information of tumor cells remains unclear. We find that CTL’s mechanosensitive ability requires the activity of the actin-organizing protein Wiskott-Aldrich Syndrome Protein (WASP). WASP activation is modulated by the mechanical properties of antigen-presenting contexts across a wide range of target cell stiffnesses and activated WASP then mediates mechanosensitive activation of early TCR signaling markers in the CTL. Our results provide a molecular link between antigen mechanosensing and CTL immune response and suggest that CTL-intrinsic cytoskeletal organizing principles enable the processing of mechanical information from diverse target cells.

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Section: Discussioncontrasting

confidence: 99%

WASP facilitates tumor mechanosensitivity in T lymphocytes

Mandal,

Melo,

Gordiichuk

et al. 2023

Preprint

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Inducible Polarized Secretion of Exosomes in T and B Lymphocytes

Calvo

Izquierdo

2020

IJMS

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Exosomes are extracellular vesicles (EV) of endosomal origin (multivesicular bodies, MVB) constitutively released by many different eukaryotic cells by fusion of MVB to the plasma membrane. However, inducible exosome secretion controlled by cell surface receptors is restricted to very few cell types and a limited number of cell surface receptors. Among these, exosome secretion is induced in T lymphocytes and B lymphocytes when stimulated at the immune synapse (IS) via T-cell receptors (TCR) and B-cell receptors (BCR), respectively. IS formation by T and B lymphocytes constitutes a crucial event involved in antigen-specific, cellular, and humoral immune responses. Upon IS formation by T and B lymphocytes with antigen-presenting cells (APC), the convergence of MVB towards the microtubule organization center (MTOC), and MTOC polarization to the IS, are involved in polarized exosome secretion at the synaptic cleft. This specialized mechanism provides the immune system with a finely-tuned strategy to increase the specificity and efficiency of crucial secretory effector functions of B and T lymphocytes. As inducible exosome secretion by antigen-receptors is a critical and unique feature of the immune system this review considers the study of the traffic events leading to polarized exosome secretion at the IS and some of their biological consequences.

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Interfacial actin protrusions mechanically potentiate killing by cytotoxic T cells

Abstract: One sentence summary: Cytotoxic T lymphocytes use F-actin-rich protrusions at the immunological synapse to potentiate perforin-and granzyme-mediated target cell killing.

Cited by 2 publications

References 63 publications

WASP facilitates tumor mechanosensitivity in T lymphocytes

WASP facilitates tumor mechanosensitivity in T lymphocytes

Inducible Polarized Secretion of Exosomes in T and B Lymphocytes

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