Cytoskeletal control of the secretory immune synapse

Douanne, Tiphaine; Griffiths, Gillian M.

doi:10.1016/j.ceb.2021.02.008

Cited by 24 publications

(17 citation statements)

References 52 publications

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“…Centrosome repositioning beneath the synaptic membrane is essential for the polarized delivery of the cytotoxic effectors of CTLs to the target cell (Douanne and Griffiths, 2021). Co-staining with anti-pericentrin and anti-GzmB Abs showed that centrosome polarization towards the IS was impaired in Spike-W-pretreated CTLs, as assessed by measuring the distance of the centrosome from the IS center (Fig.S2A; Fig.3A,B; videos 4-6).…”

Section: Resultsmentioning

confidence: 99%

“…The killing machinery of CTLs includes the lytic granules, which are lysosome-like organelles enriched in granzymes and perforin, the recently described supramolecular attack particles (Balint et al, 2020), and FasL, which is released both at the plasma membrane and in association with exosomes to trigger the Fas apoptosis pathway in target cells (Cassioli and Baldari, 2022). While the specificity of killing is dependent on cognate cell recognition by T cell antigen receptor (TCR) interaction with major histocompatibility complex-bound peptide antigen (pMHC), selectivity is ensured by the precise delivery of the cytotoxic effectors to the target cell at the immune synapse (IS), a highly specialized signaling and secretory platform that forms at the CTL interface with its target (Douanne and Griffiths, 2021; Dustin and Choudhuri, 2016). TCR engagement triggers a profound rearrangement of receptors, adhesion molecules and signaling mediators at the target cell contact, which leads to the typical bull’s eye architecture of the mature IS.…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly

Onnis

Andreano

Cassioli

et al. 2022

Preprint

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CTL-mediated killing of virally infected or malignant cells is orchestrated at a specialized intercellular junction, the immune synapse (IS). We hypothesized that SARS-CoV-2 may target IS assembly in CTLs to escape killing. We show that primary human CD8+ T cells strongly upregulate the expression of ACE2, the Spike protein receptor, during differentiation to CTLs. CTL pre-incubation with the Wuhan or Omicron Spike variants inhibits IS assembly and function, as shown by defective synaptic accumulation of TCRs and tyrosine phosphoproteins as well as defective centrosome and lytic granule polarisation to the IS, resulting in impaired target cell killing. These defects were reversed by anti-Spike antibodies that interfere with ACE2 binding and were reproduced by ACE2 engagement with Angiotensin-II or an anti-ACE2 antibody, but not by the ACE2 product Ang (1-7). These results highlight a new strategy of immune evasion by SARS-CoV-2 based on the Spike-dependent, ACE2-mediated targeting of the lytic IS to prevent the elimination of infected cells.Summary statementWe report a new mechanism of immune evasion by SARS-CoV-2 based on direct disabling CTLs to form immune synapses through Spike protein binding to ACE2. This mechanism could contribute to the failure of the immune system to control SARS-CoV-2 infection.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly

Onnis

Andreano

Cassioli

et al. 2022

Preprint

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“…Not surprisingly, several actin cytoskeleton regulators, such as actin-related proteins 2/3 (ARP2/3), hematopoietic lineage cell-specific protein 1 (HS1), transgelin-2 (TAGLN2), Diaphanous-related formin 1 (Dia1) and Formin-like 1 (FMNL1), have been shown to participate in MTOC-guided, polarized secretory traffic at the IS [ 124 , 125 ], although the contribution of all these actin cytoskeleton regulators specifically to exosome secretion has not been addressed yet. Since several recent reviews have dealt with the contribution of actin cytoskeleton reorganization to polarized secretory traffic at the IS [ 69 , 126 , 127 ], we focus on some relevant issues directly related to exosome secretion. F-actin depolymerization at the IS center controls MTOC and secretory granule polarization to the secretory domain of both CTL [ 30 , 120 ] and Th lymphocytes IS [ 128 , 129 ].…”

Section: Traffic Of Cytotoxic Granules and Mvb In T Lymphocytesmentioning

confidence: 99%

T Lymphocyte and CAR-T Cell-Derived Extracellular Vesicles and Their Applications in Cancer Therapy

Calvo

Izquierdo

2022

Cells

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Extracellular vesicles (EV) are a very diverse group of cell-derived vesicles released by almost all kind of living cells. EV are involved in intercellular exchange, both nearby and systemically, since they induce signals and transmit their cargo (proteins, lipids, miRNAs) to other cells, which subsequently trigger a wide variety of biological responses in the target cells. However, cell surface receptor-induced EV release is limited to cells from the immune system, including T lymphocytes. T cell receptor activation of T lymphocytes induces secretion of EV containing T cell receptors for antigen and several bioactive molecules, including proapoptotic proteins. These EV are specific for antigen-bearing cells, which make them ideal candidates for a cell-free, EV-dependent cancer therapy. In this review we examine the generation of EV by T lymphocytes and CAR-T cells and some potential therapeutic approaches of these EV.

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“…The synapse allows the exchange of information (molecules and vesicles) between the two cells through tightly regulated exocytic and endocytic events (8). Signaling and trafficking at the immune synapse require deep rearrangements of both the lymphocyte actin and microtubule cytoskeletons (9). On one side, the actin cytoskeleton controls the organization of antigen receptor-containing micro-clusters for coordination between trafficking and signaling and further helps generating the mechanical forces that depend on the myosin II motor (10–13).…”

Section: Introductionmentioning

confidence: 99%

Microtubules restrict F-actin polymerization to the immune synapse via GEF-H1 to maintain polarity in lymphocytes

Pineau

Pinon

Mesdjian

et al. 2022

Preprint

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Immune synapse formation is a key step for lymphocyte activation. In B lymphocytes, the immune synapse controls the production of high-affinity antibodies, thereby defining the efficiency of humoral immune responses. While the key roles played by both the actin and microtubule cytoskeletons in the formation and function of the immune synapse have become increasingly clear, how the different events involved in synapse formation are coordinated in space and time by actin-microtubule interactions is not understood. Using a microfluidic pairing device, we studied with unprecedented resolution the dynamics of the various events leading to immune synapse formation and maintenance. Our results identify two groups of events, local and global dominated, respectively, by actin and microtubules dynamics. They further highlight an unexpected role for microtubules and the GEF-H1-RhoA axis in restricting F-actin polymerization at the immune synapse to define the cell polarity axis, allowing the formation and maintenance of a unique competent immune synapse.

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Cytoskeletal control of the secretory immune synapse

Cited by 24 publications

References 52 publications

SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly

SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly

T Lymphocyte and CAR-T Cell-Derived Extracellular Vesicles and Their Applications in Cancer Therapy

Microtubules restrict F-actin polymerization to the immune synapse via GEF-H1 to maintain polarity in lymphocytes

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