Cytoskeletal tension actively sustains the migratory T‐cell synaptic contact

Kumari, Sudha; Mak, Michael; Poh, Yeh‐Chuin; Tohmé, Mira; Watson, Nicki; Melo, Mariane B.; Janssen, Erin; Dustin, Michael L.; Geha, Raif S.; Irvine, Darrell J.

doi:10.15252/embj.2019102783

Cited by 61 publications

(48 citation statements)

References 98 publications

(162 reference statements)

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“…The cytoskeletal defects of megakaryocytes are responsible for the low number of platelets in patients with WAS ( 92 ). WASP deficiency promotes T-cell cytoskeletal tension decay and phosphorylation of a serine/threonine protein kinase 4 (STK4) that usually increase T-cell migration, therefore promoting immune synapse breaking and secondary B cells dysfunction ( 93 , 94 ). WASP-deficient lymphocytes fails to differentiate into memory cells ( 95 ) and are more prone to develop DNA damages due to the loss of the Golgi-dispersal response, a recently described mechanism of cell survival after ionized radiation exsposure ( 96 ).…”

Section: Introductionmentioning

confidence: 99%

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation

et al. 2021

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A growing number of monogenic immune-mediated diseases have been related to genes involved in pathways of actin cytoskeleton remodeling. Increasing evidences associate cytoskeleton defects to autoinflammatory diseases and primary immunodeficiencies. We reviewed the pathways of actin cytoskeleton remodeling in order to identify inflammatory and immunological manifestations associated to pathological variants. We list more than twenty monogenic diseases, ranging from pure autoinflammatory conditions as familial Mediterranean fever, mevalonate kinase deficiency and PAPA syndrome, to classic and novel primary immunodeficiencies as Wiskott-Aldrich syndrome and DOCK8 deficiency, characterized by the presence of concomitant inflammatory and autoimmune manifestations, such as vasculitis and cytopenia, to severe and recurrent infections. We classify these disorders according to the role of the mutant gene in actin cytoskeleton remodeling, and in particular as disorders of transcription, elongation, branching and activation of actin. This expanding field of rare immune disorders offers a new perspective to all immunologists to better understand the physiological and pathological role of actin cytoskeleton in cells of innate and adaptive immunity.

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Section: Introductionmentioning

confidence: 99%

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation

et al. 2021

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“…A hallmark of T‐cell cytotoxic activity is exerting mechanical forces through the IS and onto target cancerous cell and vice versa, [ 7 ] whereas disturbances or loss of such forces greatly compromise CAR/TCR activation and cytotoxic function. [ 7–9 ] As seen in the conventional T‐cell study, cytotoxic T‐cell expressing TCRs can recognize and bind specific antigen molecules of peptide‐bound major histocompatibility complex (pMHC) expressed on the target cancer cell. During the process, T‐cell is highly mechanosensitive and the TCR activation and force generation are regulated by the local mechanical cues [ 10,11 ] and geometric arrangement of binding ligands.…”

Section: Introductionmentioning

confidence: 99%

The CAR T‐Cell Mechanoimmunology at a Glance

Cai

et al. 2020

Advanced Science

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Chimeric antigen receptor (CAR) T-cell transfer is a novel paradigm of adoptive T-cell immunotherapy. When coming into contact with a target cancer cell, CAR T-cell forms a nonclassical immunological synapse with the cancer cell and dynamically orchestrates multiple critical forces to commit cytotoxic immune function. Such an immunologic process involves a force transmission in the CAR and a spatiotemporal remodeling of cell cytoskeleton to facilitate CAR activation and CAR T-cell cytotoxic function. Yet, the detailed understanding of such mechanotransduction at the interface between the CAR T-cell and the target cell, as well as its molecular structure and signaling, remains less defined and is just beginning to emerge. This article summarizes the basic mechanisms and principles of CAR T-cell mechanoimmunology, and various lessons that can be comparatively learned from interrogation of mechanotransduction at the immunological synapse in normal cytotoxic T-cell. The recent development and future application of novel bioengineering tools for studying CAR T-cell mechanoimmunology is also discussed. It is believed that this progress report will shed light on the CAR T-cell mechanoimmunology and encourage future researches in revealing the less explored yet important mechanosensing and mechanotransductive mechanisms involved in CAR T-cell immuno-oncology.

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“…T cell activation requires the recognition of cognate pMHC on the surface of APCs by TCRs, generating cytoskeleton tension through nucleation of actin foci via Wiskott–Aldrich syndrome protein (WASP) and contraction of the resultant actin filaments by myosin II and leading to formation of immune synapses ( Figure 1 h) [ 31 • ].…”

Section: Mechano-regulation Of Adaptive Immunitymentioning

confidence: 99%

Unraveling the mechanobiology of immune cells

Zhang

Kim

Thauland

et al. 2020

Current Opinion in Biotechnology

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Immune cells can sense and respond to biophysical cues — from dynamic forces to spatial features — during their development, activation, differentiation and expansion. These biophysical signals regulate a variety of immune cell functions such as leukocyte extravasation, macrophage polarization, T cell selection and T cell activation. Recent studies have advanced our understanding on immune responses to biophysical cues and the underlying mechanisms of mechanotransduction, which provides rational basis for the design and development of immune-modulatory therapeutics. This review discusses the recent progress in mechanosensing and mechanotransduction of immune cells, particularly monocytes/macrophages and T lymphocytes, and features new biomaterial designs and biomedical devices that translate these findings into biomedical applications.

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Cytoskeletal tension actively sustains the migratory T‐cell synaptic contact

Cited by 61 publications

References 98 publications

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation

The CAR T‐Cell Mechanoimmunology at a Glance

Unraveling the mechanobiology of immune cells

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