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Editorial: A stake in the game: ADAM23 contributes to dendritic cell effectiveness in stimulating CD4+ T cell proliferative responses

The triggering of T cell-mediated adaptive immune responses depends on interactions between T cells and APCs, among which DCs are known to be particularly potent [1, 2]. In the secondary lymphoid organs, DCs play a major role in activating T cells by providing the initial antigenic stimulus in the form of MHCp complexes that are specifically recognized by the TCR. Although crucial for the activation of naı̈ve T cells, TCR/MHCp interactions are not sufficient to initiate proliferation and differentiation. The additional required stimuli are often provided by the same DC and represent costimulatory signals that promote T cell survival and expansion and that instruct the T cell to commit to one of the multiple effector lineages [3, 4]. These costimulatory pathways are diverse and generally entail binding of specific receptors, such as CD28 and ICOS, at the T cell surface to their ligands expressed on the DC. Combined signaling through the TCR and 1 or more costimulatory pathways results in the activation of transcriptional events that sustain the clonal expansion and survival of the activated T cells [3, 4]. Differentiation into effector cells with defined helper or cytotoxic functions is dictated by the strength of costimulation and by the cytokine milieu present when T cell priming occurs [3]. As is obvious from this basic concept, T cell activation requires the establishment of multiple molecular interactions at the interface between the T cell and the DC. Since the publication of landmark studies in the late 1990s, the structure and complexity of this interface have been recognized by the coining of the term IS [5]. Formation of the IS is crucial to optimize cross-talk between immune cells, as it allows signaling, secretion, and endocytosis events to be focused at the contact interface. The plasticity of the DC membrane, which results in the ability to form projections, allows these cells to establish multifocal synapses that are dynamically unique when compared with other APCs [6]. The initial encounter of the DC with a T cell induces a reorganization of surface receptors present at the plasma membrane, which then provides the intercellular adhesion required for subsequent events. These include semaphorins, plexins, and neuropilins, which cluster at the IS and mediate T cell priming and cytoskeletal remodeling events upon engagement [2]. The IS formation is also accompanied by active recruitment of MHCp complexes and costimulatory molecules to the contact site [5]. The binding of the T cell integrin LFA-1 to its ligand on the DC side of the IS is crucial, both for adhesive stability and for amplifying the signaling through the TCR. Reverse signaling from T cell to DC (e.g., via CD40/CD40L interactions within the IS) serves to promote further DC maturation. Formation of the IS also induces cytoplasmic events that include the activation of antiapoptotic and prosurvival pathways to ensure DC survival, as well as the recruitment of molecules that modulate the signaling events triggered at the contact site [2]. Of paramount importance for IS formation is remodeling of the actin and microtubular cytoskeleton [2, 4, 5]. Several molecules have been shown to control polarization of the actin cytoskeleton upon synapse formation. These include proteins involved in actin elongation and nucleation, such as fascin, formins, and members of the Wiskott-Aldrich syndrome protein family, deficiencies of which are associated with impairment of DC-mediated T cell activation [2]. In T cells, TCR activation-triggered calcium signaling and integrin activation have been implicated in the modulation of the actin cytoskeleton and in the acquisition of morphologic changes that are required for IS formation [4]. Microtubule reorganization has also been described as a component of IS formation that enables the focused delivery of surface receptors and soluble mediators to the synapse [2]. The details that have been elucidated to date regarding the molecular machinery responsible for T cell activation by DCs have revealed a remarkable degree