Monocytes in Immune Defense & Cell-mediated Cytotoxicity Pin Ling ( 凌 斌 ), Ph.D. ext 5632; 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 Cell- mediated immunity 1. Humoral immunity => Molecules in body fluid, e.g. Antibody (Ab) => Key player => B cells => Target extracellular microbes & toxins 2. Cell-mediated immunity => Key player => M Φ, NK, & T cells => regulate other immune cells => Target intracellular microbes, e.g. viruses, bacteria For innate immunity, it also includes Humoral & Cellular components for 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 M Φ  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

Opsonization Direct binding Recognition of bacteria by Macrophage

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 :38 AM) © 2005 Elsevier

Downloaded from: StudentConsult (on 30 August :38 AM) © 2005 Elsevier

Downloaded from: StudentConsult (on 30 August :38 AM) © 2005 Elsevier

Downloaded from: StudentConsult (on 30 August :38 AM) © 2005 Elsevier

Downloaded from: StudentConsult (on 30 August :38 AM) © 2005 Elsevier

Downloaded from: StudentConsult (on 30 August :38 AM) © 2005 Elsevier

Downloaded from: StudentConsult (on 30 August :38 AM) © 2005 Elsevier

Downloaded from: StudentConsult (on 30 August :38 AM) © 2005 Elsevier

Downloaded from: StudentConsult (on 30 August :38 AM) © 2005 Elsevier

Downloaded from: StudentConsult (on 30 August :38 AM) © 2005 Elsevier

Downloaded from: StudentConsult (on 30 August :39 AM) © 2005 Elsevier

Downloaded from: StudentConsult (on 30 August :39 AM) © 2005 Elsevier

Downloaded from: StudentConsult (on 30 August :39 AM) © 2005 Elsevier

Granuloma in pulmonary tuberculosis

Figure 8-27

Downloaded from: StudentConsult (on 30 August :39 AM) © 2005 Elsevier