Actin Engine in Immunological Synapse

Piragyte, Indre; Jun, Chang‐Duk

doi:10.4110/in.2012.12.3.71

Cited by 19 publications

(23 citation statements)

References 132 publications

(139 reference statements)

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“…In vivo , T cells undergo an extensive search for antigen in lymphoid tissues by using ameboid migration, a process that requires actin polymerization 79 . The actin cytoskeleton has, in addition, a critical role in immunological synapse formation and regulation of T‐cell function 20 . Previous studies using mutational analysis indicated that the substrate domain of Cas‐L was required for T‐cell migration, 57 but the mechanism of Cas‐L activation was not known.…”

Section: Resultsmentioning

confidence: 99%

“…Spatial organization of the immunological synapse requires f‐actin, 8 , 9 , 10 myosin IIA, 11 , 12 , 13 microtubules and dynein, 14 and the endosomal sorting complexes required for transport 15 , 16 . There is growing evidence supporting a physical link between TCR microclusters and the actin cytoskeleton, but this most fundamental connection is the most poorly understood 17 , 18 , 19 , 20 . TCR and integrin adhesion molecules organize actin polymerization, 21 , 22 , 23 which drives transport of distinct TCR and integrin microclusters toward the center of the synapse 24 , 25 , 26 , 27 .…”

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confidence: 99%

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Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

et al. 2016

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The immunological synapse formed between a T cell and an antigen presenting cell is important for cell-cell communication during T cell mediated immune responses. Immunological synapse formation begins with stimulation of the T cell receptor (TCR). TCR microclusters are assembled and transported to the center of the immunological synapse in an actin polymerization-dependent process. However, the physical link between TCR and actin remains elusive. Here we show that lymphocyte-specific Crk-associated substrate (Cas-L), a member of a force sensing protein family, is required for transport of TCR microclusters and for establishing synapse stability. We found that Cas-L is phosphorylated at TCR microclusters in an actin polymerization-dependent fashion. Furthermore, Cas-L participates in a positive feedback loop leading to amplification of Ca2+ signaling, inside-out integrin activation, and actomyosin contraction. We propose a new role for Cas-L in T cell activation as a mechanical transducer linking TCR microclusters to the underlying actin network and coordinating multiple actin dependent structures in the immunological synapse. Our studies highlight the importance of mechanotransduction processes in T cell mediated immune responses.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

et al. 2016

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“…When TCR microclusters move to the center of the contact, and the central supramolecular activation cluster (cSMAC) forms, F-actin forms a ring structure around the cSMAC and stabilizes integrin-dependent adhesive interactions between T cells and APCs (61). F-actin also relocates to the distal pole, the site that is opposite to the IS, and facilitates the formation of a distal pole complex (61, 62), although the exact picture of the dynamic change of F-actin localization is not fully established yet. The IS is a fine-tuned process; like F-actin, actin-binding proteins also traffic in T cells in a bipolar manner during IS formation.…”

Section: Discussionmentioning

confidence: 99%

LZTFL1 Upregulated by All-Trans Retinoic Acid during CD4+ T Cell Activation Enhances IL-5 Production

Hong

Promchan

Lin

et al. 2016

The Journal of Immunology

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Retinoic acids (RAs), which are metabolites of vitamin A, have been shown to be involved in multiple T cell effector responses through their binding to the retinoic acid receptor, a ligand-activated transcription factor. Since the molecular mechanism of regulation by RA is still not fully uncovered, we investigated the gene expression profile of all-trans retinoic acid (ATRA)–treated human CD4+ T cells. Leucine zipper transcription factor-like 1 (LZTFL1) was upregulated by ATRA in a dose- and time-dependent manner. The expression of LZTFL1 depended on both ATRA and TCR signaling. LZTFL1 accumulated in the plasma membrane compartment of human CD4+ T cells, and during immunological synapse (IS) formation, it transiently redistributed to the T cell and APC contact zone, indicating its role in T cell activation. Live cell imaging demonstrates that at the initial stage of IS formation, LZTFL1 is concentrated at the APC contact site, and during later stages, it relocates to the distal pole. Knockdown of LZTFL1 reduced the basal- and ATRA-induced levels of IL-5 in CD4+ T cells, and overexpression of LZTFL1 enhanced the TCR-mediated NFAT signaling, suggesting that LZTFL1 is an important regulator of ATRA-induced T cell response. Together, these data indicate that LZTFL1 modulates T cell activation and IL-5 levels.

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“…13,23 TCR stimulation results in actin polymerization. 24 For full activation, however, T cells also require ‘outside-in’ costimulation, which leads to significant rearrangement of the actin cytoskeleton and promotes accumulation of receptors and raft membrane microdomains at the interface between T cells and APCs. 10–12,25 These previous works imply that the artificial engineering of F-actin contents at the IS may mimic the signals evoked by costimulatory molecules.…”

Section: Discussionmentioning

confidence: 99%

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

et al. 2018

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Correct temporal and spatial control of actin dynamics is essential for the cytotoxic T cell effector function against tumor cells. However, little is known whether actin engineering in tumor-targeted T cells can enhance their antitumor responses, thereby potentiating the adoptive T cell therapy. Here, we report that TAGLN2, a 22-KDa actin-stabilizing protein which is physically associated with lymphocyte function-associated antigen-1 (LFA-1), potentiates the OTI TCR CD8+ T cells to kill the intercellular adhesion molecule-1 (ICAM-1)-positive/OVA-presenting E0771 cells, but not ICAM-1-negative OVA-B16F10 cells, suggesting an ‘inside-out’ activation of LFA-1, which causes more efficient immunological synapse formation between T cells and tumor cells. Notably, recombinant TAGLN2 fused with the protein transduction domain (TG2P) overcame the disadvantages of viral gene delivery, leading to a significant reduction in tumor growth in mice. TG2P also potentiated the CD19-targeted, chimeric antigen receptor (CAR)-modified T cells to kill Raji B-lymphoma cells. Our findings indicate that activating the TAGLN2–actin–LFA-1 axis is an effective strategy to potentiate the adoptive T-cell immunotherapy.

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Actin Engine in Immunological Synapse

Cited by 19 publications

References 132 publications

Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

LZTFL1 Upregulated by All-Trans Retinoic Acid during CD4+ T Cell Activation Enhances IL-5 Production

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

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