biot 307: molecular immunology

BIOT 307: MOLECULAR IMMUNOLOGY

Cells and OrgansMarch 7-9, 2011

IMMUNE CELLS

• B lymphocytes• T “• NK• Macrophages• Dendritic Cells

Antigen-presenting cells (APCs), non-specific

Antigen Specific

characteristic (See Fig. 2-2)• antigen receptors - B, T, NK• cell surface markers – all• functions - all

NATURAL KILLER (NK)

• Large granular lymphocytes• Lack cell-surface markers like B and T cells,

pattern recognition markers (PRRs), Ig or TCR gene rearrangements

• Positive for– FcR(CD16) receptor for binding to Fc of Ig

• Activated by cytokines (IL-2, -12, -15, -18) and CCL5 and migrate to inflamed or tumor tissue– Lymph nodes, peripheral blood, spleen and liver

NATURAL KILLER (NK)

• Influence specific acquired IR– Secrete IFN-γ and TNF-α neutrophil,

macrophage (Φ) activation– Activation cytokine secretion that activates NK

cells• Killing– Tumor cells– Cells infected by intracellular pathogens, e.g.,

viruses

NATURAL KILLER (NK) T CELLS

• Killing– Direct: recognize

altered MHC I, i.e., its lack, on target cells

– Two receptor superfamilies• Inhibitory• Activating

NK: Killing by Antibody Dependent Cellular Cytotoxicity (ADCC)

Killing: Indirect• Fc portion of Ab

bound to Ag on target cell binds to FcR on NK

• Fas on target cell binds to Fas ligand on NK

• Release of perforin and granzymes

ADCC FUNCTIONS IN MANY CELLS

• NK• Eosinophils• Macrophages• Monocytes• neutrophils

IMMUNE CELLS

• B lymphocytes• T “• NK• Macrophages• Dendritic Cells

Antigen-presenting cells (APCs), non-specific

Antigen Specific

characteristic (See Fig. 2-2)• antigen receptors - B, T, NK• cell surface markers – all• functions - all

MACROPHAGE (Φ)= major scavenger

ROUTE 1: monocyte into circulation inflamed tissues inflammatory Φ and DCs

ROUTE 2: Monoblast promonocyte monocyte tissue tissue (resident) macrophages (Φ) – different in different tissues

• .

MACROPHAGE (Φ)• large quantities in the spleen, lymph

nodes, alveoli, and tonsils; 50% found in the liver as Kupffer cells

• In tissue 2-3 mo..

MACROPHAGE INGESTING YEAST CELL

MACROPHAGE FUNCTIONS• Accessory• Secretory• Effector• Regulatory

MACROPHAGE FUNCTIONS• Accessory: Encounter and internalize Ag

• Endocytosis• Phagocytosis

ROUTE: APC amplifiersCell surface receptors recognize Ag

ingestion Ag processing in lysosomes cell surface presentation of peptides to T cells activated - activate specific immune response

MACROPHAGE• Varied and prolific secretory abilities– Pro-inflammatory cytokines– Attractants for neutrophils, immature

dendritic cells, natural killer cells, and activated T

– Pro-apoptotic factors– Chemokines, cytokines, lytic enzymes,

complement components, oxygen radicals, NO, bioactive lipids, interleukins 1, IL-12, TNF-α and growth factors, self-activators.

MACROPHAGE ACTIVATION• Stimulated by Th cytokines• Inflammatory promoting cytokines• Bacterial cell wall components –

lipopolysaccharide (LPS)• IFN-γ further activates Φ better functioning

• Fully activated• Larger, ruffled, gene expression of effector

molecules

MACROPHAGE ACTIVATION

NUMEROUS EFFECTOR CELL FUNCTIONS

• Ag presentation• Kill microorganisms, tumor cells• Make Φ cytokine and chemokine production• Activate T cells

Notes for slide on previous page• Effector function of phagocytosis and killing of

phagocytosed microbe• Reactive oxygen intermediates (ROIs) produced by

phagocyte oxidase from oxygen• Nitric oxide (NO) produced by inducible nitric oxide

synthase (iNOS) from arginine lysosomal enzymes• Other effector functions:• produce cytokines of innate immunity: TNF, IL-1,• Chemokines produce growth factors helping tissue

remodeling and enhance antigen presentation by increasing MHC molecules and costimulators

MACROPHAGE REGULATORY ROLES

• Control IR– T-cell proliferation• Cel-cell contract• Monokines

– Suppress lymphocyte proliferation• IFN-γ• Prostaglandins• Reactive oxygen species• NO

MACROPHAGE ROLES: IMMUNITY & INFLAMATION

1. inflammation and fever2. lymphocyte activation3. tissue reorganization4. tissue damage5. microbicidal activity6. tumoricidal activity

Some bacteria subvert

Φ function• Receptor-mediated recognition• Phagocytosis• movement into lysosome• Perturb • ROS synthesis• RNI•Acidification

• Ag processing• Ag presentation• Signaling

LEGEND FOR FIGURE ON PREVIOUS PAGE: Macrophages = sentinels and first line of defense against infection.

Bacterial pathogens have subvert Φ function (in dark blue). Microbes can interfere with receptor-mediated recognition, phagocytosis and trafficking of bacteria to degradative lysosome. Bacteria that enter Φ avoid destruction by perturbing the signaling that is required for the production of reactive oxygen intermediates (ROIs), reactive nitrogen intermediates (RNI) and acidification (H+). Interfering with Ag processing or presentation prevents Φ from alerting other cells to infectious agent. Bacterial pathogens have several mechanisms for interfering with kinase and lipid signaling within infected Φ. Perturbation of Φ signaling: alter cell survival, transcription and secretion of soluble cytokines that recruit cells coordinate their responses to clear the microbe.

MACROPHAGE FUNCTIONS