T cell adhesion triggers an early signaling pole distal to the immune synapse

Guedj, Chloé; Abraham, Nicolas; Jullié, Damien; Randriamampita, Clotilde

doi:10.1242/jcs.182311

Cited by 11 publications

(10 citation statements)

References 51 publications

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“…Interestingly, this rearward movement has also been reported (27), where F-actin quickly accumulated around IS and pushed the original T cell body away from APCs (63,64). STIM1-Orai1 cap formation on the distal side of T cell body (26), ZAP-70 accumulation on the distal side during TCR engagement (65), and other evidence postulating an antisynapse during early T cell signaling (66) further suggest a more complex spatial role of the mitochondria in calcium buffering during T cell activation than originally postulated; however, many of these studies did not directly monitor mitochondria during T cell activation.…”

Section: Discussionmentioning

confidence: 57%

Dynamic Mitochondrial Migratory Features Associated with Calcium Responses during T Cell Antigen Recognition

Raddatz

Zhou

et al. 2019

The Journal of Immunology

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A T cell clone is able to distinguish Ags in the form of peptide–MHC complexes with high specificity and sensitivity; however, how subtle differences in peptide–MHC structures translate to distinct T cell effector functions remains unknown. We hypothesized that mitochondrial positioning and associated calcium responses play an important role in T cell Ag recognition. We engineered a microfluidic system to precisely manipulate and synchronize a large number of cell–cell pairing events, which provided simultaneous real-time signaling imaging and organelle tracking with temporal precision. In addition, we developed image-derived metrics to quantify calcium response and mitochondria movement. Using myelin proteolipid altered peptide ligands and a hybridoma T cell line derived from a mouse model of experimental autoimmune encephalomyelitis, we observed that Ag potency modulates calcium response at the single-cell level. We further developed a partial least squares regression model, which highlighted mitochondrial positioning as a strong predictor of calcium response. The model revealed T cell mitochondria sharply alter direction within minutes following exposure to agonist peptide Ag, changing from accumulation at the immunological synapse to retrograde movement toward the distal end of the T cell body. By quantifying mitochondria movement as a highly dynamic process with rapidly changing phases, our result reconciles conflicting prior reports of mitochondria positioning during T cell Ag recognition. We envision applying this pipeline of methodology to study cell interactions between other immune cell types to reveal important signaling phenomenon that is inaccessible because of data-limited experimental design.

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Section: Discussionmentioning

confidence: 57%

Dynamic Mitochondrial Migratory Features Associated with Calcium Responses during T Cell Antigen Recognition

Raddatz

Zhou

et al. 2019

The Journal of Immunology

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“…immune synapse (Guedj et al, 2016). The sequestered Arf6Q67L vacuoles are located at this site and thus are reminiscent of this antisynapse.…”

Section: Discussionmentioning

confidence: 98%

Arf6 and Rab22 mediate T cell conjugate formation by regulating clathrin-independent endosomal membrane trafficking

Johnson

Wayt

Wilson

et al. 2017

Journal of Cell Science

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Endosomal trafficking can influence the composition of the plasma membrane and the ability of cells to polarize their membranes. Here, we examined whether trafficking through clathrin-independent endocytosis (CIE) affects the ability of T cells to form a cell-cell conjugate with antigen-presenting cells (APCs). We show that CIE occurs in both the Jurkat T cell line and primary human T cells. In Jurkat cells, the activities of two guanine nucleotide binding proteins, Arf6 and Rab22 (also known as Rab22a), influence CIE and conjugate formation. Expression of the constitutively active form of Arf6, Arf6Q67L, inhibits CIE and conjugate formation, and results in the accumulation of vacuoles containing lymphocyte function-associated antigen 1 (LFA-1) and CD4, molecules important for T cell interaction with the APC. Moreover, expression of the GTP-binding defective mutant of Rab22, Rab22S19N, inhibits CIE and conjugate formation, suggesting that Rab22 function is required for these activities. Furthermore, Jurkat cells expressing Rab22S19N were impaired in spreading onto coverslips coated with T cell receptor-activating antibodies. These observations support a role for CIE, Arf6 and Rab22 in conjugate formation between T cells and APCs.

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“…However, we note that although perturbing these elements certainly can improve T-cell migration, care must be taken when engineering cells to migrate better, to ensure they retain the ability for adequate activation. For instance, a number of studies have shown that MTs are not required for the immune synapse TCR formation, whereas other studies have suggested MT-dependent synapse behavior, where this may also depend on the type of MTtargeting drug, e.g., examples of immune synapse disruption under nocodazole but not vinblastine [65][66][67][68] . Thus, there likely may be ways to perturb MT stability or MT-associated signaling without loss of immune synapse function; however, either way, perturbing the contractility side of the axis, and likely other adhesion-to-motor elements as well, alleviates potential issues with altered MT dynamics and clearly shows great promise for enhancing T-cell migration in tumors.…”

Section: Discussionmentioning

confidence: 99%

Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments

et al. 2021

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Defining the principles of T cell migration in structurally and mechanically complex tumor microenvironments is critical to understanding escape from antitumor immunity and optimizing T cell-related therapeutic strategies. Here, we engineered nanotextured elastic platforms to study and enhance T cell migration through complex microenvironments and define how the balance between contractility localization-dependent T cell phenotypes influences migration in response to tumor-mimetic structural and mechanical cues. Using these platforms, we characterize a mechanical optimum for migration that can be perturbed by manipulating an axis between microtubule stability and force generation. In 3D environments and live tumors, we demonstrate that microtubule instability, leading to increased Rho pathway-dependent cortical contractility, promotes migration whereas clinically used microtubule-stabilizing chemotherapies profoundly decrease effective migration. We show that rational manipulation of the microtubule-contractility axis, either pharmacologically or through genome engineering, results in engineered T cells that more effectively move through and interrogate 3D matrix and tumor volumes. Thus, engineering cells to better navigate through 3D microenvironments could be part of an effective strategy to enhance efficacy of immune therapeutics.

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T cell adhesion triggers an early signaling pole distal to the immune synapse

Cited by 11 publications

References 51 publications

Dynamic Mitochondrial Migratory Features Associated with Calcium Responses during T Cell Antigen Recognition

Dynamic Mitochondrial Migratory Features Associated with Calcium Responses during T Cell Antigen Recognition

Arf6 and Rab22 mediate T cell conjugate formation by regulating clathrin-independent endosomal membrane trafficking

Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments

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