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Monocytes in Immune Defense & Cell-mediated Cytotoxicity • Pin Ling (凌 斌), Ph.D. ext 5632; [email protected] • References: 1. Male D., J. Brostoff, D. B Roth, and I. Roitt Immunology (7th ed., 2006), Chapters 9 & 10 Question What happens to the immune system if RAG1 or RAG2 is mutated? 1. Severe Combined Immunodeficiency Disease (SCID) 2. Lacking functional T & B cells Outline • Cell-mediated immunity • Monocytes/Macrophages in immune defense • NK & Cytotoxic T cells in immune defense • Summary & Question Humoral vs Cellmediated immunity 1. Humoral immunity => Molecules in body fluid, e.g. Antibody (Ab) => Key player => B cells => Target extracellular For innate immunity, it microbes & toxins Cellular components for 2. Cell-mediated immunity => Key player => MΦ, NK, & T cells => regulate other immune cells => Target intracellular microbes, e.g. viruses, bacteria also includes Humoral & immune defense Key Concepts in Monocytic Phagocytes in Immune Defense-I 1. Macrophages differentiate from circulating blood monocytes. 2. Macrophages are very heterogeneous in cellular activities, and may play positive or negative roles in immune defense and tissue homeostasis. 3. Tissue (Resident) & recruited macrophages respond to injury and immune stimuli. 4. Cytokines, Chemokines, & environmental stimuli modulate the phenotype of macrophages. Maturation of Macrophages Activated Macro Differentiation of Monocytes Tissue MΦ Localized MΦ Regulated by environmental stimuli Different types of tissue macrophages Roles of macrophages & DCs in immune defense Cytokines modulate the phenotype of macrophages-I Cytokines/environmental stimuli on macrophages Granuloma in pulmonary tuberculosis Cytokines modulate the phenotype of macrophages-II Th1 & Th2 cytokines act on macrophages Key Concepts in Monocytic Phagocytes in Immune Defense-II 1. Macrophages use phagocytosis to kill invading pathogens and to clean apoptotic cells. 2. Macrophages express a variety of surface receptors to interact with pathogens, other cells (apoptotic cells), or environment. 3. Opsonic receptors, like Fc (for Ab) & complment receptors, mediate indirect binding (Opsonization) to pathogens. 4. Non-opsonic receptors, like Scavenger & Toll-like receptors, mediate direct binding to pathogenic components (PAMPs). Phagocytosis of bacteria by opsonic receptors on macrophages Fc & complement receptors on macrophages for uptaking bacteria Recognition of bacteria by Macrophage Direct binding Opsonization Scavenger receptors recognize apoptotic cells Lectin-like receptors bind various sugar ligands from pathogens TLR4/MD2 and CD14 complex for LPS recognition TLR-mediated IFN-b activation against viral infection Macrophages have intracellular receptors for detecting pathogens Macrophages produce a variety of secreted molecules ROS-mediated killing bacteria in activated macrophages NOS pathway in activated macrophages Roles of activated macrophages in immunopathology Outline • Cell-mediated immunity • Monocytes/Macrophages in immune defense • NK cells & Cytotoxic T lymphocytes (CTLs) in immune defense • Summary & Question Key concepts in NK & CTL in immune defense 1. Cell-mediated cytotoxicity is an essential defense against intracellular pathogens, including viruses, some bacteria and parasites. 2. Cytotoxicity is regulated by celluar interactions, cytokines, and granule exocytosis. 3. CTLs recognize their target cells presenting Ag on MHC-I. NK cells are activated once their target cells lost MHC-I. 4. Tumor cells may also become the targets of cytotoxic cells Recognition of target cells by CTLs and NK cells Interactions between CTLs and target cells Effector functions of CTLs and CD4+ T helper cells Granule exocytosis of CTLs-I Granule exocytosis of CTLs-II Figure 8-35 CTLs induce apoptosis in target cells Ligation of Fas (CD95) or TNFR triggers apoptosis in target cells Figure 2-49 Activation of NK cells once target cells lost MHC-I 1. Virus-infected cells & tumor cells tend to lost MHC-I to avoid CTL attack. 2. NK cells are complementary to CTLs for immune defense. NK cells express a variety of inhibitory & activating receptors CD94-NKG2A CD94-NKG2C HLA-E presents peptides of MHC-I to NK cells Killer immunoglobulin-like receptors (KIRs) Ab-dependent cell-mediated cytotoxicity (ADCC) by NK cells SUMMARY 1. Macrophages are key players in innate immunity and also link to adaptive immunity. 2. Macrophages use phagocytosis to kill invading pathogens and to clean apoptotic cells. 3. NK cells also play a key role in innate immunity and function complementary to CTLs against viruses and tumors. 4. Cell-mediated cytotoxicity is an essential defense against intracellular pathogens, including viruses, some bacteria and parasites. Downloaded from: StudentConsult (on 30 August 2006 04:38 AM) © 2005 Elsevier Downloaded from: StudentConsult (on 30 August 2006 04:38 AM) © 2005 Elsevier Downloaded from: StudentConsult (on 30 August 2006 04:38 AM) © 2005 Elsevier Downloaded from: StudentConsult (on 30 August 2006 04:38 AM) © 2005 Elsevier Downloaded from: StudentConsult (on 30 August 2006 04:38 AM) © 2005 Elsevier Downloaded from: StudentConsult (on 30 August 2006 04:38 AM) © 2005 Elsevier Downloaded from: StudentConsult (on 30 August 2006 04:38 AM) © 2005 Elsevier Downloaded from: StudentConsult (on 30 August 2006 04:38 AM) © 2005 Elsevier Downloaded from: StudentConsult (on 30 August 2006 04:38 AM) © 2005 Elsevier Downloaded from: StudentConsult (on 30 August 2006 04:38 AM) © 2005 Elsevier Downloaded from: StudentConsult (on 30 August 2006 04:39 AM) © 2005 Elsevier Downloaded from: StudentConsult (on 30 August 2006 04:39 AM) © 2005 Elsevier Downloaded from: StudentConsult (on 30 August 2006 04:39 AM) © 2005 Elsevier Granuloma in pulmonary tuberculosis Figure 8-27 Downloaded from: StudentConsult (on 30 August 2006 04:39 AM) © 2005 Elsevier