2. Monocytes in Immune Defense & Cell-mediated Cytotoxicity Pin Ling ( 凌 斌 ), Ph.D. ext 5632; lingpin@mail.ncku.edu.tw References: 1. Male D., J. Brostoff, D. B Roth, and I. Roitt Immunology (7th ed., 2006), Chapters 9 & 10

3. 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

4. Outline Cell-mediated immunity Monocytes/Macrophages in immune defense NK & Cytotoxic T cells in immune defense Summary & Question

5. 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

6. 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.

7. Maturation of Macrophages Activated Macro

8. Differentiation of Monocytes Tissue MΦ  Localized M Φ  Regulated by environmental stimuli

9. Different types of tissue macrophages

10. Roles of macrophages & DCs in immune defense

11. Cytokines modulate the phenotype of macrophages-I

12. Cytokines/environmental stimuli on macrophages

13. Granuloma in pulmonary tuberculosis

14. Cytokines modulate the phenotype of macrophages-II

15. Th1 & Th2 cytokines act on macrophages

16. 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).

17. Phagocytosis of bacteria by opsonic receptors on macrophages

19. Fc & complement receptors on macrophages for uptaking bacteria

20. Opsonization Direct binding Recognition of bacteria by Macrophage

21. Scavenger receptors recognize apoptotic cells

22. Lectin-like receptors bind various sugar ligands from pathogens

23. TLR4/MD2 and CD14 complex for LPS recognition

24. TLR-mediated IFN-b activation against viral infection

25. Macrophages have intracellular receptors for detecting pathogens

26. Macrophages produce a variety of secreted molecules

27. ROS-mediated killing bacteria in activated macrophages

28. NOS pathway in activated macrophages

29. Roles of activated macrophages in immunopathology

30. Outline Cell-mediated immunity Monocytes/Macrophages in immune defense NK cells & Cytotoxic T lymphocytes (CTLs) in immune defense Summary & Question

31. 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

32. Recognition of target cells by CTLs and NK cells

33. Interactions between CTLs and target cells

34. Effector functions of CTLs and CD4+ T helper cells

35. Granule exocytosis of CTLs-I

36. Granule exocytosis of CTLs-II

37. Figure 8-35

38. CTLs induce apoptosis in target cells

39. Ligation of Fas (CD95) or TNFR triggers apoptosis in target cells

40. Figure 2-49

41. 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.

42. NK cells express a variety of inhibitory & activating receptors CD94-NKG2A CD94-NKG2C

43. HLA-E presents peptides of MHC-I to NK cells

44. Killer immunoglobulin-like receptors (KIRs)

45. Ab-dependent cell-mediated cytotoxicity (ADCC) by NK cells

46. 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.

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61. Granuloma in pulmonary tuberculosis

62. Figure 8-27

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