T Lymphocyte Migration: The Influence of Interactions via Adhesion Molecules, the T Cell Receptor, and Cytokines

Hauzenberger, Dan; Klominek, Julius; Bergström, Sten-Erik; Sundqvist, Kristina

doi:10.1615/critrevimmunol.v15.i3-4.60

Cited by 54 publications

(32 citation statements)

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“…In fact, synergy between cytokines and chemokines has been previously observed in proliferation, differentiation, and survival assays as well as in migration experiments. 27,[52][53][54][55] Our findings showing increased migration when cells were stimulated with 2-AG and IL-3 as well as 2-AG and G-CSF strengthen the idea to further investigate the role that 2-AG may have in combination with cytokines in proliferation, differentiation, or survival of leukemic progenitor cells.…”

Section: Discussionmentioning

confidence: 62%

Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol

Jordà

Verbakel

Valk

et al. 2002

Blood

145

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Cb2 is a novel protooncogene encoding the peripheral cannabinoid receptor. Previous studies demonstrated that 2 distinct noncoding first exons exist: exon-1A and exon-1B, which both splice to proteincoding exon-2. We demonstrate that in retrovirally induced murine myeloid leukemia cells with proviral insertion in Cb2, exon-1B/exon-2 Cb2 messenger RNA levels have been increased, resulting in high receptor numbers. In myeloid leukemia cells without virus insertion in this locus, low levels of only exon-1A/exon-2 Cb2 transcripts were present and receptors could not be detected. To elucidate the function of Cb2 in myeloid leukemia cells, a set of in vitro experiments was carried out using 32D/G-CSF-R (granulocyte colony-stimulating factor receptor) cells transfected with exon-1B/exon-2 Cb2 complementary DNA and a myeloid cell line carrying a virus insertion in Cb2 (ie, NFS 78). We demonstrate that a major function of the Cb2 receptor is stimulation of migration as determined in a transwell assay. The cannabinoid receptors belong to the superfamily of 7-transmembrane G protein-coupled receptors (GPCRs). Several GPCRs have been shown to be involved in cell growth and oncogenesis as the result of aberrant expression. [5][6][7] Examples of GPCRs with transforming ability are the ␣1B-adrenergic, 8 thrombin, 9 and serotonin 1c receptors 10 and the receptor encoded by MAS oncogene. 11,12 Our previous observation that Cb2 is a common virus integration site suggests that aberrant expression of this 7-transmembrane receptor may be a critical event in transformation in certain cases of leukemia. 3 The protein-coding region of Cb2 is located on a single exon (exon-2) of approximately 4 kilobases. Recently we identified 2 distinct 5Ј noncoding exons (ie, exon-1A and exon-1B) previously designated exon-1 and exon-1Ј, respectively. 3 In the study presented here we first carried out experiments to investigate Cb2 messenger RNA (mRNA) transcripts and protein expression in leukemic cells with or without retroviral insertion in the Cb2 locus. Secondly, we performed studies to determine the function of the peripheral cannabinoid receptor when overexpressed in myeloid cells.GPCRs have been related to many functions, including cell proliferation, maturation, survival, apoptosis, or migration. 6,13,14 In the present study, we investigated the function of the peripheral cannabinoid receptor when overexpressed on myeloid cells (ie, 32D/G-CSF-R [granulocyte colony-stimulating factor receptor]) in which we overexpressed exon-1B/exon-2 Cb2 splice variant and a myeloid leukemia cell line containing a virus insertion in the Cb2 locus, NFS 78. We also wished to determine which of the large panel of Cb2 ligands that have been identified previously is the true agonist of the receptor. We investigated the effects of natural (␦ 8 24 ) cannabinoids. We show that 2-AG is the most potent agonist for the Cb2 receptor and that a major function of 2-AG is stimulation of migration. We further studied whether 2-AG acts as a chemotactic or chemokinetic age...

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Section: Discussionmentioning

confidence: 62%

Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol

Jordà

Verbakel

Valk

et al. 2002

Blood

145

View full text Add to dashboard Cite

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“…Efficient T cell activation critically depends on integrinmediated adhesion. Whereas adhesion to the cell surface protein ICAM-1 is crucial for T cell/APC interactions (18,19), ␤1 integrin-mediated adhesion to extracellular matrix proteins such as fibronectin determines the capacity of T cells to migrate and infiltrate inflamed tissues (28,29). As shown in Figure 2a, teriflunomide caused a significant and concentrationdependent reduction of CD3-induced T cell adhesion to ICAM-1.…”

Section: Resultsmentioning

confidence: 97%

Disruption of the interaction of T cells with antigen‐presenting cells by the active leflunomide metabolite teriflunomide: Involvement of impaired integrin activation and immunologic synapse formation

Zeyda

Poglitsch

Geyeregger

et al. 2005

Arthritis & Rheumatism

102

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Objective. Leflunomide, a potent diseasemodifying antirheumatic drug of the isoxazole class, exhibits antiinflammatory, antiproliferative, and immunosuppressive effects by largely unknown mechanisms, although alterations of pyrimidine synthesis have been proposed. Successful immune responsiveness requires T cell activation by interaction with antigen-presenting cells (APCs), and integrin activation and formation of an immunologic synapse (IS). In this study, we evaluated the impact of the active leflunomide metabolite teriflunomide on T cell integrin activation, evolution of the IS, and antigen-specific formation of stable T cell/ APC conjugates.Methods. Effects of pharmacologic concentrations of teriflunomide on CD3/CD28-and lymphocyte function-associated antigen 1-induced signal transduction and activation of primary human T cells were investigated. Furthermore, T cells were stimulated with superantigen-and antigen-pulsed APCs to study relocalization of molecules to the IS and T cell/APC conjugate formation.Results. Teriflunomide inhibited T cell receptor (TCR)/CD3-mediated calcium mobilization, but other critical T cell signaling events, including activation of MAPK and NF-B, remained unaltered. In contrast, inhibition of TCR/CD3-triggered ␤1,2 integrin avidity and integrin-mediated costimulation (outside-in signaling) by teriflunomide revealed a striking interference with integrin function that was independent of altered pyrimidine synthesis. Moreover, teriflunomide abolished molecule relocalization to the IS and induction of T cell/APC conjugates.Conclusion. These data show that the active metabolite of leflunomide prevents the interaction of T cells with APCs to form an IS. Since IS formation is crucial for eliciting an immune response, this novel mechanism could underlie the beneficial effects of leflunomide in immune-mediated disorders such as rheumatoid arthritis.

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“…This assay was designed to investigate whether TIL show migratory responses to immobilised vitronectin, that is, haptotaxis as well as chemotaxis or chemokinesis in response to soluble vitronectin (Hauzenberger et al, 1995). One microlitre of 0.02% BSA/RPMI as a control and different concentrations of vitronectin also in RPMI were applied to the surface of glass slides and then the chemotaxis membranes were coated by floating the membrane on the surface of the slide with the underside in contact with the coating solution overnight at 41C.…”

Section: Haptotaxis Assaymentioning

confidence: 99%

Vitronectin in human hepatic tumours contributes to the recruitment of lymphocytes in an αvβ3-independent manner

et al. 2006

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The degree of lymphocyte infiltration is a prognostic factor in liver cancer, but to date the mechanisms by which lymphocytes infiltrate into and are retained in hepatic tumours are poorly understood. We hypothesised that the extracellular matrix glycoprotein vitronectin, a major component of the stroma of hepatic tumours, might play a role in the recruitment and retention of tumourinfiltrating lymphocytes (TIL). Thus, we investigated the ability of vitronectin to support migration and adhesion of TIL isolated from hepatocellular carcinoma and colorectal hepatic metastases. Soluble vitronectin-induced dose-dependent migration of TIL in in vitro chemotaxis and haptotaxis assays and vitronectin in tissue sections was able to support TIL adhesion to tumour stroma. Neither adhesion nor migration was inhibited by a function blocking mAb against the major vitronectin receptor avb3 and we were unable to detect avb3 on TIL in vitro or in vivo on tumour tissue. However, TIL did express high levels of urokinase-type plasminogen activator receptor (uPAR) and inhibitory antibodies and amiloride both significantly inhibited TIL adhesion to vitronectin and reduced transendothelial migration of lymphocytes across liver endothelium in vitro. Thus, we provide evidence that vitronectin in liver tumours can support the recruitment and retention of effector lymphocytes by an uPAR-dependent mechanism.

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T Lymphocyte Migration: The Influence of Interactions via Adhesion Molecules, the T Cell Receptor, and Cytokines

Cited by 54 publications

References 0 publications

Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol

Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol

Disruption of the interaction of T cells with antigen‐presenting cells by the active leflunomide metabolite teriflunomide: Involvement of impaired integrin activation and immunologic synapse formation

Vitronectin in human hepatic tumours contributes to the recruitment of lymphocytes in an αvβ3-independent manner

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