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T-Cell Mediated Cytotoxicity

T-Cell Mediated Cytotoxicity - BIO/MI 494G Fall 2008 T-cell...

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BIO/MI 494G Fall 2008 T-cell Mediated Cytotoxicity I. Introduction 1. Intracellular pathogens, e.g. viruses, certain bacteria 2. CD8 cytotoxic T-lymphocytes (CTL) 3. Activation of naïve CD8 T-cell II. Mechanism of activation of naïve CD8 T-cell 1. Three means of activation III. Steps in CTL mediated lysis of target cells 1. Initial binding 2. Conjugated formation 3. Delivery of lethal hit 4. Detachment of CTL 5. Target cell death IV. Cellular mechanism of killing 1. Apoptosis V. Polarization of CTL towards target cell 1. Formation of supramolecular activation complex (immunological synapse) VI. Biochemical mechanism of CTL induced target cell apoptosis 1. Lytic granules a. Perforin b. Granzymes c. Granulysin 2. Mechanism of action of lytic granules 3. Fas/Fas ligand induced apoptosis
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Antigen recognition Lymphocyte activation Differentiation ".""'"'~ Activation of macro phages, B cells, other cells Killing of infected "target cells"; macrophage activation Memory CD8+ Teell Lymphoid organs Peripheral tissues FIGURE 9-2 Phases of T cell responses. Antigen recognition by T cells induces cytokine (e.g., IL-2) secretion, clonal expansion as a result of IL-2-induced autocrine cell proliferation, and differentiation of the T cells into effector cells or memory cells. In the effector phase of the response, the effector C04+ T cells respond to antigen by producing cytokines that have several actions, such as the activation of macrophages and B lymphocytes, and C08+ CTLs respond by killing other cells. APC, antigen-presenting cell.
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Fig. 1.27 Mechanism of host defense against intracellular infection by viruses. Cells infected by viruses are recognized by specialized T cells called I. cytotoxic T cells, which kill the infected cells directly. The killing mechanism involves the activation of enzymes known as caspases, which contain cysteine in their active site and cleave after aspartic acid. These in turn activate a cytosolic nuclease in the infected cell, which cleaves host and viral DNA. Panel a is a transmission electron micrograph showing the plasma membrane of a cultured CHO cell (the Chinese hamster ovary cell line) infected with influenza virus. Many virus particles can be seen budding from the cell surface. Some of these have been labeled with a monoclonal antibody that is specific for a viral protein and is coupled to gold particles, which appear as the solid black dots in the micrograph. Panel b is a transmission electron micrograph of a virus-infected cell M surrounded by cytotoxic T lymphocytes. Note the close apposition of the membranes of the virus- infected cell and the T cell (T) in the upper left corner of the micrograph, and the clustering of the cytoplasmic organelles in the T cell between its nucleus and the point of contact with the infected cell.
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