T cell activation and function require a structured engagement of antigen-presenting cells. These cell contacts are characterized by two distinct dynamics in vivo: transient contacts resulting from promigratory junctions called immunological kinapses or prolonged contacts from stable junctions called immunological synapses. Kinapses operate in the steady state to allow referencing to selfpeptide-MHC (pMHC) and searching for pathogen-derived pMHC. Synapses are induced by T cell receptor (TCR) interactions with agonist pMHC under specific conditions and correlate with robust immune responses that generate effector and memory T cells. High-resolution imaging has revealed that the synapse is highly coordinated, integrating cell adhesion, TCR recognition of pMHC complexes, and an array of activating and inhibitory ligands to promote or prevent T cell signaling. In this review, we examine the molecular components, geometry, and timing underlying kinapses and synapses. We integrate recent molecular and physiological data to provide a synthesis and suggest ways forward.
Immunological synapses are initiated by signaling in discrete T cell receptor (TCR) microclusters and play an important role in T cell differentiation and effector functions. Synapse formation involves orchestrated motion of microclusters toward the center of the contact area with the antigen-presenting cell. Microcluster movement is associated with centripetal actin flow, but the role of motor proteins is unknown. Here we show that myosin IIA was necessary for complete assembly and movement of TCR microclusters and that activated myosin IIA was recruited to the synapse. In the absence of myosin IIA or its ATPase activity, T cell signaling was interrupted downstream of Lck and the synapse was destabilized. Thus, TCR signaling and subsequent immunological synapse formation are active processes dependent on myosin IIA.
Summary The BimEL tumor suppressor is a potent pro-apoptotic BH3-only protein. We found that in response to survival signals BimEL was rapidly phosphorylated on three serine residues in a conserved degron, facilitating binding and degradation via the F-box protein βTrCP. Phosphorylation of the BimEL degron was executed by Rsk1/2 and promoted by the Erk1/2-mediated phosphorylation of BimEL on Ser69. Compared to wild type BimEL, a BimEL phosphorylation mutant unable to bind βTrCP was stabilized and consequently potent at inducing apoptosis by the intrinsic mitochondrial pathway. Moreover, although non-small cell lung cancer (NSCLC) cells often become resistant to gefitinib (a clinically relevant tyrosine kinase inhibitor that induces apoptosis through BimEL), silencing of either βTrCP or Rsk1/2 resulted in BimEL-mediated apoptosis of both gefitinib-sensitive and gefitinib-insensitive NSCLC cells. Our findings reveal that βTrCP promotes cell survival in cooperation with the ERK-RSK pathway, by targeting BimEL for degradation.
SUMMARY Cytolytic granule mediated killing of virus-infected cells is an essential function of cytotoxic T lymphocytes. Analysis of lytic granule delivery shows that the granules can take long or short paths to the secretory domain where they are released. Both paths utilize the same intracellular molecular events, which have different spatial and temporal arrangements in each path and are regulated by the kinetics of downstream Ca2+ mediated signaling. Rapid and robust signaling causes swift granule concentration near the MTOC and subsequent delivery by the polarized MTOC directly to the secretory domain - the shortest and fastest path. Indolent signaling leads to late recruitment of granules that move along microtubules to the periphery of the synapse and then move tangentially to fuse at the outer edge of the secretory domain - a longer path. The short pathway is associated with faster granule release and more efficient killing than the long pathway.
SUMMARY Cytotoxic lymphocytes kill target cells by releasing the content of secretory lysosomes at the immune synapse. To obtain information on the dynamics and control of cytotoxic immune synapses we imaged human primary, live natural killer cells on lipid bilayers carrying ligands of activation receptors. Formation of an organized synapse was dependent on the presence of the β2 integrin ligand ICAM-1. Ligands of co-activation receptors 2B4 and NKG2D segregated into central and peripheral regions, respectively. Lysosomal protein LAMP-1 that was exocytosed during degranulation accumulated in a large and spatially stable cluster, which overlapped with a site of membrane internalization. Lysosomal compartments reached the plasma membrane at focal points adjacent to centrally accumulated LAMP-1. Imaging of fixed cells revealed that perforin-containing granules were juxtaposed to an intracellular compartment where exocytosed LAMP-1 was retrieved. Thus, cytotoxic immune synapses include a central region of bidirectional vesicular traffic, which is controlled by integrin signaling.
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