Intracellular signaling required for CCL25-stimulated T cell adhesion mediated by the integrin 4 1 (original) (raw)
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Adhesion shapes T cells for prompt and sustained T-cell receptor signalling
The EMBO Journal, 2010
During T-cell migration, cell polarity is orchestrated by chemokine receptors and adhesion molecules and involves the functional redistribution of molecules and organelles towards specific cell compartments. In contrast, it is generally believed that the cell polarity established when T cells meet antigen-presenting cells (APCs) is controlled by the triggered T-cell receptor (TCR). Here, we show that, during activation of human T lymphocytes by APCs, chemokines and LFA-1 establish cell polarity independently of TCR triggering. Chemokine-induced LFA-1 activation results in fast recruitment of MTOC and mitochondria towards the potential APC, a process required to amplify TCR Ca 2 þ signalling at the upcoming immunological synapse, to promote nuclear translocation of transcriptional factor NFATc2 and boost CD25 expression. Our data show that the initial adhesive signals delivered by chemokines and LFA-1 shape and prepare T cells for antigen recognition.
The Journal of Immunology, 2006
Adhesion-and degranulation-promoting adapter protein (ADAP) is required in TCR-induced activation and proliferation of peripheral T cells. Loss of ADAP also impairs TCR-initiated inside-out activation of the integrin LFA-1 (CD11a/CD18, ␣ L  2 ). In this study, we demonstrate that ADAP-deficient CD4/CD8 double-positive (DP) cells have a diminished ability to proliferate, and that these DP thymocytes up-regulate CD69 poorly in vivo. Moreover, in both MHC class I-and class II-restricted TCR transgenic models, loss of ADAP interferes with both positive and negative selection. ADAP deficiency also impairs the ability of transgenebearing DP thymocytes to form conjugates with Ag-loaded presenting cells. These findings suggest that ADAP is critical for thymocyte development and selection.
1996
T cell development in the thymus requires the establishment of stable interactions with cellselecting elements such as the cortical epithehum followed by a regulated movement of selected progenitors to the medulla. Cell adhesion and migration are mediated by integrins in a number of biological systems though little is known regarding their function in the thymus. We demonstrated previously that immature CD31~ l~ double positive human thymocytes adhere avidly to FN via the integrin, VLA4. We now demonstrate that the interaction of mature CD3hiCD69 hi thymic subsets with FN triggers migration rather than firm adhesion. Migration requires the engagement of VLA4 in cooperation with VLA5 and both receptors regulate the persistence and directionality of movement. While migration capability is linked to maturation state, ligand concentration determines the efficiency of migration. In fact, FN and the alternatively sphced CS1 site are predominant in the thymic medulla, suggesting an instructive role of this ECM protein in vivo. Our studies identify a novel VLA4 and VLA5/FNmediated pathway likely to be involved in regulating cell traffic between the cortex and medulla of the thymus. Moreover, the data provides evidence that VLA4 exists in at least two functional states at distinct stages ofT cell development. While different states of VLA4 activation have been described on cell lines, this represents the first evidence supporting a biological significance for this integrin property. p ositioning of developing thymocytes within the thymic cortex and medulla as well as the regulation of their ability to move from one region to another are crucial to T cell differentiation. Thus a stable interaction with cortical epithelial cells facihtating the recognition of MHC/peptide complexes is a prerequisite for the positive selection of immature double positive T cells (1). In fact, there is evidence that positive selection within the cortex is limited by contact with these selecting elements (2, 3) underscoring the importance of migratory events leading T cell progenitors to the epithehum. Subsequent events of maturation, including negative selection, appear to occur in the medulla involving bone marrow-derived antigen-presenting cells as well as a phenotypically distinct medullary epithelium (4). Implicit in these compartment-specific events is the programmed detachment of developing thymocytes from the cortical epithelium and the regulated movement of those committed to the mature single positive phenotype to the medulla. While much has been learned about the function of the T cell receptor (TCPQ and the costimulatory mole-cules, CD4 and CD8, these molecules cannot directly mediate stable cell-cell adhesion or migration. In contrast, the role of interactions mediated by integrin adhesion molecules expressed by thymocytes with extracellular matrix (ECM) 1 proteins such as fibronectin (FN) in thymocyte motihty, has not been elucidated.
Rac Regulates Integrin-Mediated Spreading and Increased Adhesion of T Lymphocytes
1998
Leukocyte adhesion to the extracellular matrix (ECM) is tightly controlled and is vital for the immune response. Circulating lymphocytes leave the bloodstream and adhere to ECM components at sites of inflammation and lymphoid tissues. Mechanisms for regulating T-lymphocyte-ECM adhesion include (i) an alteration in the affinity of cell surface integrin receptors for their extracellular ligands and (ii) an alteration of events following postreceptor occupancy (e.g., cell spreading). Whereas H-Ras and R-Ras were previously shown to affect T-cell adhesion by altering the affinity state of the integrin receptors, no signaling molecule has been identified for the second mechanism. In this study, we demonstrated that expression of an activated mutant of Rac triggered dramatic spreading of T cells and their increased adhesion on immobilized fibronectin in an integrin-dependent manner. This effect was not mimicked by expression of activated mutant forms of Rho, Cdc42, H-Ras, or ARF6, indicating the unique role of Rac in this event. The Rac-induced spreading was accompanied by specific cytoskeletal rearrangements. Also, a clustering of integrins at sites of cell adhesion and at the peripheral edges of spread cells was observed. We demonstrate that expression of RacV12 did not alter the level of expression of cell surface integrins or the affinity state of the integrin receptors. Moreover, our results indicate that Rac plays a role in the regulation of T-cell adhesion by a mechanism involving cell spreading, rather than by altering the level of expression or the affinity of the integrin receptors. Furthermore, we show that the Rac-mediated signaling pathway leading to spreading of T lymphocytes did not require activation of c-Jun kinase, serum response factor, or pp70 S6 kinase but appeared to involve a phospholipid kinase.
Developmental Immunology, 2000
T cell precursors homed to thymus develop in close contact with stromal cells. Among them, thymic epithelial cells (TEC) are known to exert dominant roles in their survival and functional shaping. Key molecules mediating TEC/thymocytes interactions include cytokines and growth factors secreted by the two cell types and adhesion receptors mediating cell contact. Signaling events triggered in thymocytes by adhesion to epithelial cells have been extensively investigated, whereas little is known on the opposite phenomenon. We have previously investigated this issue in a co-culture system composed of TEC cultures derived from human normal thymus and heterologous thymocytes. We demonstrated that thymocytes adhere to TEC involving [ and [34 integrins and induce the clustering of (z3[ and 6134 heterodimers at the TEC surface. In addition thymocyte adhesion was followed by activation of NF-zB and NF-IL6 gene transciption factors and enhanced IL-6 production. The two latter phenomena were reproduced by the cross-linking of the 3, 6, [31 and [34 integrins, thus implying that the 3131 and z6134 heterodimers can signal during thymocyte adhesion. We have extended our previous work investigating in the same experimental setting the inducing activity of non stimulated or activated policlonal or clonal mature T cells as representative of the more mature thymocyte subset. We found that adhesion of unstimulated T cell i) involved 1, but not 4 integrin functions at the surface ii) induced the clustering of 3[31, but not c21 heterodimers at the TEC surface and iii) up-regulated the nuclear binding activity of NF-r,B transcription factor and the IL-6 secretion. We propose that 31 and 64 heterodimers are induced to cluster at the TEC surface recognizing yet unknown cellular ligands differentially expressed during T cell development.
Rap1A-deficient T and B cells show impaired integrin-mediated cell adhesion
Molecular and cellular biology, 2006
Studies in tissue culture cells have demonstrated a role for the Ras-like GTPase Rap1 in the regulation of integrin-mediated cell-matrix and cadherin-mediated cell-cell contacts. To analyze the function of Rap1 in vivo, we have disrupted the Rap1A gene by homologous recombination. Mice homozygous for the deletion allele are viable and fertile. However, primary hematopoietic cells isolated from spleen or thymus have a diminished adhesive capacity on ICAM and fibronectin substrates. In addition, polarization of T cells from Rap1-/- cells after CD3 stimulation was impaired compared to that of wild-type cells. Despite this, these defects did not result in hematopoietic or cell homing abnormalities. Although it is possible that the relatively mild phenotype is a consequence of functional complementation by the Rap1B gene, our genetic studies confirm a role for Rap1A in the regulation of integrins.
Immunology Letters, 2004
Dynamic regulation of integrin-mediated adhesion is central to lymphocyte trafficking and antigen recognition. The small GTPase Rap1 is a potent stimulator of leukocyte integrins through modulation of affinity and avidity. In addition, lymphocyte Rap1 has unique abilities to trigger cell polarization and enhance cell motility. These characteristics of Rap1 contribute to adhesive interactions with antigen-presenting cells (APC) and the vascular endothelium. In the process of elucidating the molecular mechanisms of Rap1-mediated integrin activation, we have identified a novel Rap1-binding molecule, regulator of adhesion and cell polarization enriched in lymphoid tissues (RAPL). RAPL is predominantly expressed in immune cells, and mediates Rap1-triggered integrin activation upon TCR engagement and chemokine stimulation. Importantly, Rap1/RAPL signaling cooperatively regulates cell polarization and integrin activation. The linkage between cell polarization and integrin activation through Rap1/RAPL signaling likely provides immune cells with their dynamic trafficking capability.