CXCL12 Regulates through JAK1 and JAK2 Formation of Productive Immunological Synapses

Cascio, Graciela; Martín-Cófreces, Noa B.; Rodrı́guez-Frade, José Miguel; López-Cotarelo, Pilar; Criado, Gabriel; Pablos, José L.; Rodrı́guez-Fernández, José Luis; Sánchez-Madrid, Francisco; Mellado, Mario

doi:10.4049/jimmunol.1402419

Cited by 27 publications

(27 citation statements)

References 64 publications

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“…Moreover, localization of CCR5 and CXCR4 at the IS and exposure to their ligands presented by APCs might desensitize the chemokine receptor signal and stabilize the contact site . In line with this, interfering with G protein‐dependent CXCR4 and JAK1/2 signaling correlated with reduced actin polymerization at the contact site, altered structure of the IS, and mislocalization of the microtubule‐organizing center …”

Section: Chemokine Receptors As Co‐stimulatory Molecules For Efficienmentioning

confidence: 69%

“…Distinct co-stimulatory activities have been attributed to the chemokines CCL5, CCL19, CCL21, and CXCL12. [90][91][92][93][94][95][96][97] T cell costimulation via TCR and CXCR4 was shown to enhance the expression of the activation markers CD69, CD25, and CD154 to increase T cell proliferation, as well as to augment the production of the cytokines IL-2, IFN-, IL-4, and IL-10. 90-92 CXCR4-driven IL-10 and IL-2 secretion was further noted to enhance activation of the transcription factor AP-1.…”

Section: Chemokine Receptors As Co-stimulatory Molecules For Efficienmentioning

confidence: 99%

“…91 In line with this, interfering with G protein-dependent CXCR4 and JAK1/2 signaling correlated with reduced actin polymerization at the contact site, altered structure of the IS, and mislocalization of the microtubule-organizing center. 95 CXCR4 directly interacts with the TCR, allowing CXCR4 to utilize the ITAMs of TCR to signal through ZAP70. 92 CXCR4 and TCR costimulation also stabilizes SLP76 cluster formation facilitating its phosphorylation by ZAP70.…”

Section: Chemokine Receptors As Co-stimulatory Molecules For Efficienmentioning

confidence: 99%

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Beyond migration—Chemokines in lymphocyte priming, differentiation, and modulating effector functions

Laufer

Legler

2018

Journal of Leukocyte Biology

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Chemokines and their receptors coordinate the positioning of leukocytes, and lymphocytes in particular, in space and time. Discrete lymphocyte subsets, depending on their activation and differentiation status, express various sets of chemokine receptors to be recruited to distinct tissues. Thus, the network of chemokines and their receptors ensures the correct localization of specialized lymphocyte subsets within the appropriate microenvironment enabling them to search for cognate antigens, to become activated, and to fulfill their effector functions. The chemokine system therefore is vital for the initiation as well as the regulation of immune responses to protect the body from pathogens while maintaining tolerance towards self. Besides the well investigated function of orchestrating directed cell migration, chemokines additionally act on lymphocytes in multiple ways to shape immune responses. In this review, we highlight and discuss the role of chemokines and chemokine receptors in controlling cell-to-cell contacts required for lymphocyte arrest on endothelial cells and immunological synapse formation, in lymphocyte priming and differentiation, survival, as well as in modulating effector functions.

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Section: Chemokine Receptors As Co‐stimulatory Molecules For Efficienmentioning

confidence: 69%

Section: Chemokine Receptors As Co-stimulatory Molecules For Efficienmentioning

confidence: 99%

Section: Chemokine Receptors As Co-stimulatory Molecules For Efficienmentioning

confidence: 99%

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Beyond migration—Chemokines in lymphocyte priming, differentiation, and modulating effector functions

Laufer

Legler

2018

Journal of Leukocyte Biology

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“…Although T cells express both CXCR4 and CCR7, CCR7/CXCR4 heterodimers are not detected on these cells during immunological synapse formation. Interestingly, CXCR4 is recruited to the peripheral SMAC whereas CCR7 is not . The use of different cell types, distinct technical approaches.…”

Section: Chemokine Receptor Dimerization/oligomerization: a Potentialmentioning

confidence: 99%

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Martínez-Muñoz

Villares

Rodrı́guez-Fernández

et al. 2018

Journal of Leukocyte Biology

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The chemokines direct leukocyte recruitment in both homeostatic and inflammatory conditions, and are therefore critical for immune reactions. By binding to members of the class A G protein-coupled receptors, the chemokines play an essential role in numerous physiological and pathological processes. In the last quarter century, the field has accumulated much information regarding the implications of these molecules in different immune processes, as well as mechanistic insight into the signaling events activated through their binding to their receptors. Here, we will focus on chemokine receptors and how new methodological approaches have underscored the role of their conformations in chemokine functions. Advances in biophysical-based techniques show that chemokines and their receptors act in very complex networks and therefore should not be considered isolated entities. In this regard, the chemokine receptors can form homo- and heterodimers as well as oligomers at the cell surface. These findings are changing our view as to how chemokines influence cell biology, identify partners that regulate chemokine function, and open new avenues for therapeutic intervention.

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“…β2M is an established prognostic factor in CLL, and reduction in β2M levels is associated with prolonged progression-free survival. 29 Recent studies demonstrated that activation of JAK and its downstream signal transducer and activator of transcription (STAT) pathway affects the levels of CXCL12/CXCR4 30 , 31 and CCL2 chemokines 32 . Treatment with ruxolitinib suppressed the expression of several chemokine and cytokines, suggesting that gene expression in CLL cells mobilized from their microenvironment 33 is different from that of steady state circulating CLL cells.…”

Section: Discussionmentioning

confidence: 99%

Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial

Jain

Keating

Renner

et al. 2017

The Lancet Haematology

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Summary Background Disease-related symptoms impair the quality of life of countless patients with chronic lymphocytic leukemia (CLL) who do not require systemic therapy. Currently available therapies are not specifically aimed at symptom control. Because stimulation of the B-cell receptor activates Janus kinase (JAK)-2 in CLL cells and the JAK2 inhibitor ruxolitinib improves symptoms of patients with myelofibrosis, we hypothesized that ruxolitinib would improve disease-related symptoms in CLL patients. Methods Ruxolitinib (10 mg twice daily) was administered to symptomatic CLL patients who did not require systemic therapy for CLL. Scores on the brief fatigue inventory (BFI), CLL module of the MD Anderson symptom inventory (MDASI) and symptom-associated interference in daily activities (interference score; IS), were assessed prior to treatment and after 3 months of treatment. Plasma cytokine/chemokine levels were measured at baseline and at 3 months. Findings Forty-one CLL patients (25 untreated and 16 previously treated) were enrolled. Thirty-two (78%) of the participants experienced ≥20% reduction in the average BFI score or in the average MDASI score. 59% of the participants had ≥2 units reduction in worst fatigue score in 24 hours as assessed by the BFI. The mean percentage reductions in BFI, MDASI, and IS scores were >42% (p<0.0001). Improvements in the three symptom scores correlated with reductions in levels of IL-6, C-reactive protein, CXCL10, osteopontin, TNF-α, ICAM-1/CD54, VCAM-1/CD106, and beta-2 microglobulin. Furthermore, treatment with ruxolitinib increased and then decreased lymphocyte counts to baseline levels or lower. Grade 3/4 cytopenias were recorded in three patients. Interpretation In CLL patients, ruxolitinib significantly improved disease-related symptoms, reduced cytokine and chemokine levels, and increased and then decreased lymphocyte counts, likely through mobilization followed by apoptosis of CLL cells. Further studies aimed at testing the therapeutic efficacy of ruxolitinib in CLL are warranted. Funding Supported by the Incyte Corp., MD Anderson Cancer Center Support Grant CA016672 and Award Number P01 CA049639 from the National Cancer Institute.

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CXCL12 Regulates through JAK1 and JAK2 Formation of Productive Immunological Synapses

Cited by 27 publications

References 64 publications

Beyond migration—Chemokines in lymphocyte priming, differentiation, and modulating effector functions

Beyond migration—Chemokines in lymphocyte priming, differentiation, and modulating effector functions

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial

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