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The immunological synapse (IS) is a specialised cell-cell adhesion that mediates antigen acquisition and regulates the activation of lymphocytes. Initial studies of the IS showed a structure composed of stable supra-molecular activation clusters (SMAC) organised during the interaction of helper T lymphocytes with B lymphocytes, working as antigen presenting cells. A central SMAC of coalesced T cell receptors (TCRs) and a peripheral SMAC for cell-cell adhesion were observed. IS with similar structure was later described during antigen acquisition by B cells and during the interaction of NK cells with target and healthy cells. More recent research developed with microscopy systems that improve the spatial and temporal resolution has showed the complex molecular dynamics at the IS that governs lymphocyte activation. Currently, the IS is seen as a three-dimensional structure where signalling networks for lymphocyte activation and endosomal and cytoskeleton machinery are polarised. A view has emerged in which dynamic microclusters of signalling complexes are composed of molecular components attached to the plasma membrane and other components conveyed on sub-synaptic vesicles transported to the membrane by cytoskeletal fibers and motor proteins. Much information is nonetheless missing about how the dynamics of the endosomal compartment, the cytoskeleton, and signalling complexes are reciprocally regulated to achieve the function of lymphocytes. Experimental evidence also suggests that the environment surrounding lymphocytes exposed to different antigenic challenge regulates IS assembly and functional output, making an even more complex scenario still far from being completely understood. Also, although some signalling molecular components for lymphocyte activation have been identified and thoroughly studied, the function of other molecules has not been yet uncovered or deeply characterised. This research topic aims to provide the reader with the latest information about the molecular dynamics governing lymphocyte activation. These molecular dynamics dictate cell decisions. Thus, we expect that understanding them will provide new avenues for cell manipulation in therapies to treat different immune-related pathologies.

cytoskeleton dynamics --- intracellular signalling --- Immunological Synapse --- endosomal dynamics

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Cytotoxic lymphocytes, comprised of NK cells and cytotoxic T cells, play a pivotal role in immune defense. By directed release of perforin-containing lytic granules, NK and cytotoxic T cells can eradicate pathogen-infected, tumorigenic, and otherwise stressed cells. By the virtue of cytokine and chemokine secretion, they can influence other cells of the immune system. Through these processes, cytotoxic lymphocytes also contribute to the maintenance of immune homeostasis. In recent years, much progress has been made with respect to the mechanisms by which cytotoxic lymphocytes develop, differentiate, and exert their effector functions. In a clinical perspective, a wide variety of mutations impairing cytotoxic lymphocyte development and/or function have been associated with immunodeficiency and severe diseases in humans. Aberrant activity of cytotoxic T cells and/or NK cells has been linked to an increased susceptibility to viral infections, persistent inflammation, cancer and autoimmunity. In addition, lymphocyte cytotoxic activity may be harnessed therapeutically to target tumor cells in different adoptive cellular therapy regimes, or through the use of recombinant antibodies. Still, a number of questions remain in regards to how cytotoxic lymphocytes develop, their relationships and plasticity, as well as the mechanisms dictating target cell discrimination, lytic granule release and induction of target cell death. In this Research Topic we encourage submission of research articles, reviews, perspectives, or methods on cytotoxic lymphocyte development and function, their relation to the pathogenesis or treatment of different diseases, as well as comparison between similarities and/or differences in their effector functions. Considering the clinical significance of NK cells and cytotoxic T cells, we aim to provide a range of articles summarizing the current knowledge on the identification and elucidation of the mechanisms governing cytotoxic lymphocyte activity.

Microbiology & Immunology --- Biology --- Health & Biological Sciences --- secretory lysosomes --- NK cells --- hemophagocytic histiocytosis --- immune therapy --- granzyme --- lytic granules --- Cytotoxicity --- anti-tumor response --- Immunological Synapse --- Perforin