1. BIOT 307: MOLECULAR IMMUNOLOGY Cells and Organs March 7-9, 2011

2. 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

3. 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

4. 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

5. NATURAL KILLER (NK) T CELLS Killing – Direct: recognize altered MHC I, i.e., its lack, on target cells – Two receptor superfamilies Inhibitory Activating

6. NK: Killing by Antibody Dependent Cellular Cytotoxicity (ADCC) Killing: Indirect F c portion of Ab bound to Ag on target cell binds to F c R on NK Fas on target cell binds to Fas ligand on NK Release of perforin and granzymes

7. ADCC FUNCTIONS IN MANY CELLS NK Eosinophils Macrophages Monocytes neutrophils

9. 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

10. 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.

11. 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..

12. MACROPHAGE INGESTING YEAST CELL

13. MACROPHAGE FUNCTIONS Accessory Secretory Effector Regulatory

14. MACROPHAGE FUNCTIONS Accessory: Encounter and internalize Ag Endocytosis Phagocytosis ROUTE: APC amplifiers Cell surface receptors recognize Ag  ingestion  Ag processing in lysosomes  cell surface presentation of peptides to T cells  activated - activate specific immune response

15. 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.

16. 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

18. MACROPHAGE ACTIVATION

19. NUMEROUS EFFECTOR CELL FUNCTIONS Ag presentation Kill microorganisms, tumor cells Make Φ cytokine and chemokine production Activate T cells

21. 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

22. MACROPHAGE REGULATORY ROLES Control IR – T-cell proliferation Cel-cell contract Monokines – Suppress lymphocyte proliferation IFN-γ Prostaglandins Reactive oxygen species NO

23. MACROPHAGE ROLES: IMMUNITY & INFLAMATION 1.inflammation and fever 2.lymphocyte activation 3.tissue reorganization 4.tissue damage 5.microbicidal activity 6.tumoricidal activity

24. Some bacteria subvert Φ function Receptor-mediated recognition Phagocytosis movement into lysosome Perturb ROS synthesis RNI Acidification Ag processing Ag presentation Signaling

25. 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.

26. MACROPHAGE FUNCTIONS