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Chapter 14 Cell-Mediated Effector Responses Cell-mediated immunity: Detect and eliminate cells that harbor intracellular pathogens. Ag-specific cells – CD4+ T cells, CD8+ T cells Ag-nonspecific cells – NK cells macrophages neutrophils eosinophils Cytotoxic T Cells Two major categories of cell-mediated immune responses: - Effector cells that have direct cytotoxic activity. - Effector cells that mediate delayed-type hypersensitivity (DTH) reactions Three types of effector T cells: 1. CD4+ TH1cells 2. CD4+ TH2 cells 3. CD8+ CTLs Characteristics: - less stringent activation requirements - increased expression of cell-adhesion molecules - production of both membrane-bound and soluble effector molecules - The CD45RO isoform associates with the TCR complex and CD4/CD8 much better than does the CD45RA isoform. - CD2 LFA-3, LFA-1 ICAMs - The FasL, perforins, and granzymes mediate target cell destruction by the CTLs. - Membrane-bound TNFb and soluble IFNg and GM-CSF promote macrophage activation by the TH1 cell. - The membrane-bound CD40L and soluble IL-4, IL-5, IL-6, and IL-10 play a role in B cell activation by the TH2 cell. Generation of Effector CTLs B7 CD28 Tumor-Cell Destruction by a CTL CTL tumor cell CTL-Mediated Killing of Target Cells perforin monomers & granzyme proteases Cell-Mediated Pore Formation in Target-Cell Membrane fusion release iCa++ insertion Perforin Pore on a Red Blood Cell - Perforin exhibits sequence homology with C9, and the pores formed by perforin are similar to those observed in complement-mediated lysis. - The perforin pores facilitate entry of granzyme proteases into the cell. - Granzymes activate an apoptotic pathway within the cell. CTL Can Use Fas to Lyze a Target Cell CTL-mediated Killing Depends on Perforin, Fas, or A Combination of the Two CTL-Mediated Apoptotic Pathways Caspase: cysteine, aspartate protease Natural Killer Cells Natural Killer (NK) Cells: - 5 - 10% of the recirculating lymphocyte population - No immunization is required. No memory - a population of large granular lymphocytes - constitutively cytotoxic, always having large granules - involved in the defense against viruses and tumors - Activity is stimulated by IFNa, IFNb, and IL-12. - express CD16 (FcgRIII) - do not express TCR/CD3 - Recognition is not MHC-restricted. - normal in RAG-1, RAG-2, and SCID mice - Cytotoxicity depends on perforin and granzymes. Time Course of Viral Infection NK-Cell Receptors Activation Receptors: NKR-P1 (a C-type lectin recognizing carbohydrates) Inhibitory Receptors: CD94/NKG2 (recognizing HLA-E with an HLA peptide) KIR (> 50 members; specific for one or a limited number of polymorphic products of particular HLA loci) Opposing-signals Model of NK Activity KIR: killing inhibitory receptor AR: activation receptor Ab-Dependent Cell-Mediated Cytotoxicity (ADCC) Experimental Assessment of Cell-mediated Cytotoxicity Mixed Lymphocyte Reaction (MLR) Cell-mediated Lympholysis (CML) Graft versus Host Reaction (GVHR) Mixed Lymphocyte Reaction (MLR) Cell-Mediated Lympholysis (CML) Delayed-Type Hypersensitivity Overview of the Delayed Type Hypersensitivity (DTH) Response Formation of Granuloma Role of IFNg in Host Defense against Intracellular Pathogens Survival of the Intracellular Pathogen Chapter 15 Leukocyte Migration and Inflammation Lymphocyte Recirculation Routes General Structures of the 4 Families of Cell-Adhesion Molecules (CAM) Cell Adhesion Molecules (CAM) Four Sequential but overlapping Steps in Neutrophil Extravasation Cell-Adhesion Molecules and Chemokines Involved in the 1st 3 Steps of Neutrophil extravasation A Lymph-Node Postcapillary Venule with High Endothelium Numerous Lymphocytes Bound to the Surface of a High Endothelial Venule (HEV) Naïve T Cells Tend to Home to Secondary Lympoid Tissues through Their HEV Regions Effector T Cells Expressing Particular Homing Receptors Will Home to particular Tertiary Extralymphoid Tissues Extravasation of a Naïve T Cell through a High Endothelial Venule into a Lymph Node Mediators of Inflammation 1. Chemokines 2. Plasma Enzyme Mediators kinin system clotting system fibrinolytic system complement system 3. Lipid Inflammatory Mediators 4. Cytokine Inflammatory mediators Tissue Damage Induces Formation of Plasma Enzyme Mediators by the Kinin System, the Clotting System, and the Fibrinolytic System The Breakdown of Membrane Phospholipids Generates Mediators of Inflammation (proinflammatory cytokines) Overview of the Cells and Mediators Involved in a Local Acute Inflammatory Response Overview of the Organs and Mediators Involved in a Systemic Acute-Phase Response The End