Insights into the Mechanism for Dictating Polarity in Migrating T-Cells

Niggli, Verena

doi:10.1016/b978-0-12-800178-3.00007-5

Cited by 24 publications

(20 citation statements)

References 194 publications

(288 reference statements)

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“…Chemokines—upon activation of their corresponding receptor—induce intracellular signaling cascades that result in cell activation and motility that includes G-protein–mediated and –independent pathways (47, 48). As expected from its failure to induce chemotaxis, CXCL14 alone did not induce transient elevations of intracellular Ca 2+ concentrations, which are typically observed in chemokine receptors coupling to G αi proteins, whereas CXCL12 alone showed expected response profiles ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4

et al. 2017

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The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100–300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone. CXCL14 did not activate CXCR4-expressing cells (i.e., failed to trigger chemotaxis and Ca2+ mobilization, as well as signaling via ERK1/2 and the small GTPase Rac1); however, CXCL14 bound to CXCR4 with high affinity, induced redistribution of cell-surface CXCR4, and enhanced HIV-1 infection by >3-fold. We postulate that CXCL14 is a positive allosteric modulator of CXCR4 that enhances the potency of CXCR4 ligands. Our findings provide new insights that will inform the development of novel therapeutics that target CXCR4 in a range of diseases, including cancer, autoimmunity, and HIV.—Collins, P. J., McCully, M. L., Martínez-Muñoz, L., Santiago, C., Wheeldon, J., Caucheteux, S., Thelen, S., Cecchinato, V., Laufer, J. M., Purvanov, V., Monneau, Y. R., Lortat-Jacob, H., Legler, D. F., Uguccioni, M., Thelen, M., Piguet, V., Mellado, M., Moser, B. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4.

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Section: Resultsmentioning

confidence: 99%

“…Small GTPases, including Rho, Cdc42, and Rac isoforms, control cell polarization in the front and rear (uropod), which is a prerequisite for cell migration (48). Primary human T cells that were exposed to 1 nM CXCL12 already induced T-cell polarization as evidenced by F-actin staining (Fig.…”

Section: Resultsmentioning

confidence: 99%

Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4

et al. 2017

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“…Ezrin is an AKAP that is abundantly expressed in T lymphocytes, and it is the only AKAP that has been functionally characterized in these cells. Ezrin is important for establishing the polarity toward chemokine signals and uropod formation during T cell migration [147][148][149] and moreover, participates in T cell activation by fine tuning the microtubule network during IS formation through its constitutive interaction with the scaffold protein disks large homolog 1 [84,150,151]. Ezrin also plays a role in the cAMP-PKA pathway, as it binds to PKA type I and localizes it to the lipid rafts during T cell activation, thereby terminating TCR signaling [83].…”

Section: Effector Pathways-pka and Epac1mentioning

confidence: 99%

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

Arumugham

Baldari

2017

Journal of Leukocyte Biology

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T Lymphocyte activation involves a substantial reorganization of the membranous and intracellular compartments. Signaling complexes assemble and dismantle in a highly ordered fashion in both compartments and orchestrate the activation of T cells with high sensitivity and specificity. TCR ligation leads to a short burst of cAMP production, which is centrally required for T cell activation; however, sustained elevations in intracellular cAMP concentrations are immunosuppressive. Emerging evidence of the existence of local cAMP pools gleaned from studies on other cell types suggests that cAMP compartmentalization may account, in part, for these opposing effects. Whereas cAMP compartmentalization has been identified as a central factor in the control of the cAMP-dependent processes in other cell types, this has, as yet, not been addressed in T lymphocytes. In this review, we discuss the role of cAMP in T cell activation and differentiation, with an emphasis on the effects mediated by the cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC)1, and on the regulatory proteins that may control the generation of local cAMP pools in T cells. We also present an overview of the available tools to image cAMP production at the subcellular level and discuss how bacterial adenylate cyclase (AC) toxins that are known to generate local cAMP pools can be exploited to address the role of cAMP compartmentalization in T cell activation.

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“…This structure contains many of the components classically described at the immunological synapse and constitutes a real signaling complex, as revealed by detection of tyrosine phosphorylation. Interestingly, accumulation of some molecules at the rear of the cell has already been reported in the case of the uropod (Niggli, 2014), the DPC (Cullinan et al, 2002) and the distal cap (Barr et al, 2008). The classic components of the DPC and the distal cap are also found at the antisynapse.…”

Section: Discussionmentioning

confidence: 81%

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

Guedj

Abraham

Jullié

et al. 2016

Journal of Cell Science

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The immunological synapse forms at the interface between a T cell and an antigen-presenting cell after foreign antigen recognition. The immunological synapse is considered to be the site where the signaling cascade leading to T lymphocyte activation is triggered. Here, we show that another signaling region can be detected before formation of the synapse at the opposite pole of the T cell. This structure appears during the first minute after the contact forms, is transient and contains all the classic components that have been previously described at the immunological synapse. Its formation is independent of antigen recognition but is driven by adhesion itself. It constitutes a reservoir of signaling molecules that are potentially ready to be sent to the immunological synapse through a microtubuledependent pathway. The antisynapse can thus be considered as a pre-synapse that is triggered independently of antigen recognition.

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Insights into the Mechanism for Dictating Polarity in Migrating T-Cells

Cited by 24 publications

References 194 publications

Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4

Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

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

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