Integrin adhesion receptors are critical for antigen recognition by T cells and for regulated recirculation and trafficking into and through various tissues in the body. T-cell receptor (TCR) signaling induces rapid increases in integrin function that facilitate T-cell activation by promoting stable contact with antigen-presenting cells and extracellular proteins in the environment. In this review, we outline the molecular mechanisms by which the TCR signals to integrins and present a model that highlights four key events: (i) initiation of proximal TCR signals nucleated by the linker for activated T cells (LAT) adapter protein and involving Itk, phospholipase C-gamma1, Vav1, and Src homology 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa; (ii) transmission of integrin activation signals from the LAT signalosome to integrins by protein kinase (PK) C and the adapter protein, adhesion and degranulation-promoting adapter protein; (iii) assembly of integrin-associated signaling complexes that include PKD, the guanosine triphosphatase Rap1 and its effectors, and talin; and (iv) reorganization of the actin cytoskeleton by WAVE2 and other actin-remodeling proteins. These events coordinate changes in integrin conformation and clustering that result in enhanced integrin functional activity following TCR stimulation.
"Intriguingly, studies of CD4 T cells revealed that Zap70 catalytic activity was not required for integrin activation, but rather that Zap70 plays a catalyticindependent role in integrin activation (Au-Yeung et al., 2010). The Zap70(AS) model therefore provides an unprecedented opportunity for examining the role of integrin vs TCR mediated events during the formation of the immunological synapse as TCR activation is required for integrin activation (Burbach et al., 2007). This is particularly interesting since integrin activation alone has been shown to trigger polarisation of both centrosome and secretory granules to the immunological synapse in Natural Killer (NK) cells; although both activating receptor and integrin activation are required for degranulation (Bryceson et al., 2005; March and Long, 2011; Bryceson et al., 2009) as well as remodelling of synaptic actin required for cytokine secretion (Brown et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: T cell receptor (TCR) activation leads to a dramatic reorganisation of both membranes and receptors as the immunological synapse forms. Using a genetic model to rapidly inhibit Zap70 catalytic activity we examined synapse formation between cytotoxic T lymphocytes and their targets. In the absence of Zap70 catalytic activity Vav-1 activation occurs and synapse formation is arrested at a stage with actin and integrin rich interdigitations forming the interface between the two cells. The membranes at the synapse are unable to flatten to provide extended contact, and Lck does not cluster to form the central supramolecular activation cluster (cSMAC). Centrosome polarisation is initiated but aborts before reaching the synapse and the granules do not polarise. Our findings reveal distinct roles for Zap70 as a structural protein regulating integrin-mediated control of actin vs its catalytic activity that regulates TCR-mediated control of actin and membrane remodelling during formation of the immunological synapse. DOI: http://dx.doi.org/10.7554/eLife.01310.001
"Naïve T-cells constantly move through lymph nodes via high endothelial venules (HEVs) which ensure their exposure to antigens in an environment conducive to optimal stimulation . The necessary cellular and cell to extra cellular matrix interactions are mediated by a large family of αβ-integrins, in particular the α4 integrins (α4β1 and α4β7), which direct peri- and extra-vascular lymphocyte trafficking [9,11,12]. It is known that expression levels of alpha-integrins can be modified by a number of endogenous signals, including the localised effect of cytokines such as interferons [13,14] and biochemical abnormalities . "
[Show abstract][Hide abstract] ABSTRACT: Alpha integrins play an important role in cell to cell and cell to extra-cellular matrix interactions required for an effective T-lymphocyte-mediated immune response, however little is known about age related differences in expression of alpha integrins on T-cells in humans. We here measured alpha-4 (alpha4) integrin (CD49d) expression on T-lymphocytes via peripheral blood sampling, comparing parameters between cohorts of young and old adults. No age-related differences were found for the absolute numbers of T-cells, although the percentage of CD4+ T-cells in older adults was significantly greater and the percentage of CD8+ T-cells lower than in younger cohorts. Percentage and absolute numbers of CD3+ T-cells co-expressing CD49d were significantly lower in older adults compared to younger cohorts, and the percentage of gated CD4+ and CD8+ cells that co-labelled positively for CD49d was also reduced in this group. There were no age-related differences in circulating levels of cytokines (Type I interferons) that are known to regulate cell surface integrin expression. Reduced expression of alpha integrins on T-cells may be an early indicator of the loss of homeostatic control that occurs with ageing, contributing to diminished effector T-cell responses during senescence.
"Integrins are well characterized as critical mediators of cellular adhesion (Burbach et al., 2007), and the decreased binding of Sh2d1a À/À T cells to antigen-activated B cells could result from SAP-mediated effects on integrin function. Alternatively, SAP may participate in distinct mechanisms of cell adhesion involving other surface adhesive receptors. "
[Show abstract][Hide abstract] ABSTRACT: CD4(+) T cells deficient in signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) exhibit a selective impairment in adhesion to antigen-presenting B cells but not dendritic cells (DCs), resulting in defective germinal center formation. However, the nature of this selective adhesion defect remained unclear. We found that whereas T cell:DC interactions were primarily integrin dependent, T cell:B cell interactions had both an early integrin-dependent phase and a sustained phase that also required SAP. We further found that the SLAM family member CD84 was required for prolonged T cell:B cell contact, optimal T follicular helper function, and germinal center formation in vivo. Moreover, both CD84 and another SLAM member, Ly108, mediated T cell adhesion and participated in stable T cell:B cell interactions in vitro. Our results reveal insight into the dynamic regulation of T cell:B cell interactions and identify SLAM family members as critical components of sustained T cell:B cell adhesion required for productive humoral immunity.
Ivonne Gamper, David Fleck, Meltem Barlin, Marc Spehr, Sara El Sayad, Henning Kleine, Sebastian Maxeiner, Carmen Schalla, Gülcan Aydin, Mareike Hoss, David W Litchfield, B. Luscher, Martin Zenke, Antonio Sechi,
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