A dynamic immunological synapse mediates homeostatic TCR‐dependent and ‐independent signaling

Abstract

For homeostasis, T cells integrate non-cognate TCR-dependent and -independent signals to survive and weakly proliferate. In contrast to antigen-specific, stable, and long-lived contacts, signaling in short-lived homeostatic interactions depends upon the coordination of ongoing T-cell migration on the surface of DC and signaling at the cell-cell junction.To mimic peripheral tissues and analyze how T-cell migration and cell-cell signaling are integrated, we used live-cell imaging and 3-D reconstruction of fixed conjugates between DO11.10 T cells and DC in 3-D low-density collagen matrices. T cells simultaneously maintained amoeboid migration and polarized towards the DC, leading to a fully dynamic interaction plane that delivered signals for homeostatic T-cell survival and proliferation. The contact plane comprised three zones, the actin-rich leading edge poor in signal but driving migration, a mid-zone mediating TCR/MHC-induced signal associated with proliferation, and the rear uropod mediating predominantly MHC-independent signals. Thus a dynamic immunological synapse with distinct signaling sectors enables moving T cells to serially sample resident tissue cells and acquire molecular information ''en passant''.Key words: Immunological synpase . Migration . T-cell homeostasis Supporting Information available online IntroductionLymphocyte recirculation and amoeboid migration within secondary lymphoid tissues are mandatory for effective immune surveillance. In secondary lymphoid organs, T cells utilize amoeboid migration along fibroblastic reticular cells as guidance cues to rapidly scan APC for cognate antigen [1,2]. Whereas the role of migration in scanning cells for their antigenic repertoire is well established, its role in T-cell activation and signal induction is less clear. On the one hand, in vitro models suggest that the recognition of antigenic peptide leads to migratory arrest [3] and the formation of a concentrically segregated interaction plane with a peripheral ring of adhesion molecules surrounding a central accumulation of TCR, the immunological synapse (IS) [4,5]. Conversely, the most powerful APC, DC, activate T cells via both stably adhesive and migratory contacts, depending on signal strength and phase of T-cell priming [6][7][8][9] and do not induce a segregated IS [10,11]. In a lipid bilayer model, the concept of productive TCR signaling despite T-cell migration is suggested by intermittent episodes of T-cell migration, which are associated with enhanced TCR signaling and IL-2 secretion [12]. Thus, the spectrum of activating T-cell/APC interactions is diverse and T-cell migration appears to contribute to rather than interfere with signal induction. However, as adhesive and migratory contact phases alternate sequentially in most experimental models, the specific topography and function of migratory phases remain unclear.In contrast to antigen-specific contacts, in vivo interactions between T cells and DC that do not present cognate antigen are Due to their intrinsic dynamics coupled to signal i...

Wiskott–Aldrich syndrome protein controls antigen‐presenting cell‐driven CD4+ T‐cell motility by regulating adhesion to intercellular adhesion molecule‐1

“…Instead, at the contact with APC, WASP‐deficient CD4 + T cells displayed an abnormally sustained migrating morphology characterized by an active leading edge and an elongated uropod. It has been shown that DC‐mediated T‐cell survival is dependent on cell‐to‐cell contact and that it may be driven by signalling originating from the uropod . It would therefore be interesting to test whether the elongated uropod observed in WASP‐deficient T cells contributes to their high propensity to survive at the contact with iDC.…”

“…However, WASP deficiency resulted in a loose confinement of high‐affinity LFA‐1 to the mid‐cell focal zone and a dispersion towards the uropod. During T‐cell scanning of DC surfaces, LFA‐1 is dynamically redistributed from the leading edge to the mid‐cell zone where it forms a signalling platform . WASP deficiency might therefore affect the spatial organization of LFA‐1 signalling.…”

“…It has been shown that DC-mediated T-cell survival is dependent on cell-to-cell contact and that it may be driven by signalling originating from the uropod. 27 It would therefore be interesting to test whether the elongated uropod observed in WASP-deficient T cells contributes to their high propensity to survive at the contact with iDC. In our in vitro setting, the enhanced motility and the elongated morphology of WASP-deficient T cells did not permit them to reach further distances and to contact more DC.…”

“…During T-cell scanning of DC surfaces, LFA-1 is dynamically redistributed from the leading edge to the mid-cell zone where it forms a signalling platform. 27 WASP deficiency might therefore affect the spatial organization of LFA-1 signalling. Previous studies have brought to light the concept that the spatial confinement and the dynamics of intermediate-affinity and high-affinity LFA-1 pools are controlled by physical links with the actin cytoskeleton.…”

HIV-1-Induced Small T Cell Syncytia Can Transfer Virus Particles to Target Cells through Transient Contacts

“…The spread of virus between infected and susceptible target cells can take place via several pathways, including: release of cell-free virus particles which are then stochastically encountered by a target cell; sequestration of virus particles by dendritic cells and subsequent delivery of these particles to a target cell (a process termed trans -infection [ 1 ]); and the process of cell-to-cell transmission, whereby an infected cell directly interacts with a target cell, thus forming a transient adhesion structure known as the virological synapse (VS; [ 2 , 3 ]), which facilitates transfer of newly released viral particles. Such interactions are thought to occur most frequently in secondary lymphoid tissue, such as in lymph nodes and the gut-associated lymphoid tissue (GALT), where high cell density and migratory scanning behavior of T cells, facilitated by the architecture of the stromal environment, provide conditions conducive to controlled cell–cell interactions, including antigen presentation through the immunological synapse [ 4 , 5 , 6 , 7 ].…”