2. Cells, Tissues, & Organs of The Immune System 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), Chapter 2 2. Abbas, A, K. et.al, Cellular and Molecular Immunology (6th ed., 2007), Chapter 3

3. Outline Cells of the Immune SystemCells of the Immune System Anatomy & Functions of Lymphoid Tissues & Organs Summary & Question

4. Key concepts about immune cells 1. The principle cells of the immune system: Antigen-presenting cells  Lymphocytes => Effector cells 2. All immune cells are derived from “Hematopoietic stem cells” in Bone Marrow (BM) (& Fetal liver during fetus). 3. Immune cells are divided into two major lineages: => Lymphoid & Myeloid => Multiple cell types => express distinct “Surface molecules (markers)” => Classification 4. Development and differentiation of different cell types depend on “Cell Interactions and Cytokines”.

5. Figure 1-3 Cells of the Immune System-I 1. Originated from Bone Marrow (BM) 2. Two major lineages: - Lymphoid - Myeloid 3. NK cells - Large Granular Lymphocytes (LGL) NK => LGL

6. Cells of the Immune System-II T lymphocytes are first derived from BM and further educated in Thymus for maturation.

7. Cells of innate immunity-I 1. Innate immune cells are derived from Bone Marrow. 2. Their primary function is to identify and kill microbes. Antigen-presenting cells (APCs) additionally function to present Ag to and activate lymphocytes. 3. Innate immune cells recognize the common microbial structures PAMPs through Pattern-Recognition Receptors (PRRs) -limited diversity.

8. Innate immune cells are classified as following: - Monocyte/Macrophage - Dendritic cell (DC) - Polymorphonuclear granulocyte (PMN; Neutrophil, Eosinophil, Basophil) - Mast cell - NK cells (lymphocyte) => Killing virus-infected cells & tumors Classes of innate immune cells

9. Development of monocytes & granulocytes 1. Myelopoiesis – Development of myeloid cells. 2. Cytokines from stromal cells, myeloid, & lymphoid cells are involved in this process.

10. Bruce A. BeutlerJules A. HoffmannRalph M. Steinman The Nobel Prize in Physiology or Medicine 2011 The Nobel Prize in Physiology or Medicine 2011 was divided, one half jointly to Bruce A. Beutler and Jules A. Hoffmann "for their discoveries concerning the activation of innate immunity" and the other half to Ralph M. Steinman "for his discovery of the dendritic cell and its role in adaptive immunity".

11. Identification of cell populations 1. Molecules on or in cells => Identification & Classification e.g. CD3, CD4, CD8…. 2. Methods: (1) Immunofluorecence (2) Flow Cytometry & Sorting (3) ELISPOT

12. Identification & isolation of cell populations

13. Maturation of Macrophages Activated Macro

14. Key concepts of Monocytes/Macrophages 1. Relatively long-lived and distributed throughout the whole body. 2. Engulf and kill pathogens by phagocytosis. 3. Express various receptors to recognize different pathogens, e.g. PRR, Scavenger receptor,….etc. 4. Trigger inflammation and Antigen presentation

16. Phagocytosis by innate immunity

17. Ag-presenting cells (APCs) link the innate & adaptive immune systems

18. Polymorphonuclear Granulocytes: Neutrophils 1. Comprise over 95% of granulocytes 2. Short-lived (2-3 days) 3. Multi-lobed nucleus 4. Kill pathogens by phagocytosis & releasing cytotoxic substances.

19. Basophils & mast cells: critical for immunity against parasites

20. Eosinophils

21. Dendritic cells (DCs) as Ag-presenting cells (APCs) FDC:Follicular DC

22. Key concepts of Dendritic Cells (DCs) 1. Most effective Ag-presenting cells linking innate and adaptive immunity 2. High MHC-II expression on DCs 3. Several types of DCs: (1) Myeloid DCs (also known as conventional DCs) (2) Lymphoid DCs => Plasmacytoid DCs (3) Lymphoid organ-specific DCs: Follicular DCs in Lymph nodes (lacking MHC-II) Interdigitating Dcs in Lymph nodes & Thymus

26. Cells of Adaptive immunity 1. Lymphocytes are the key players of the adaptive immunity. 2. Lymphocytes are able to specifically recognize and respond to diverse antigens. => Antigen (Ag) receptors on lymphocytes => Specificity (Clone), Diversity (Repertoire: total number of Ag-specific lymphocytes in an individual; 10 7-9 ), & Memory 3. Lymphocytes are classified into three major groups: - B cells => Antibodies => Humoral immunity - T cells => Multiple subtypes => Cell-mediated immunity & Regulate other immune cells - NK cells => Innate immunity

27. Classes of Lymphocytes 1. B cells => Plasma cells => Abs 2. T cells: - T helper cells - T cytotoxic cells - T regulatory cells => suppress immune responses 3. NK cells 4. Subtypes in each class

28. T cells vs B cells

29. Lymphocytes Small Lymphocytes Large Granular Lymphocytes

30. Plasma Cells-Ab Secretion

31. Outline Cells of the Immune System Anatomy & Functions of Lymphoid Tissues & OrgansAnatomy & Functions of Lymphoid Tissues & Organs Summary & Question

32. Primary lymphoid organs: BM & Thymus => Lymphocyte development, selection, & maturation. 2nd lymphoid organs: Lymphoid nodes & Spleen => Lymphocyte activation & effector functions BM  Other immune cells Eg. DCs, Macrophages, PMNs

33. The Lymphatic System Link to the blood circulation system

34. Bone Marrow 1. The site of generation of all immune and blood cells <= Hematopoietic Stem Cell 2. Provides Cell-cell interactions and Cytokines for the development of all immune cells. <= Stromal reticular cells & other cells

35. B cell development in the Bone Marrow

36. Thymus-I 1. The site of T cell maturation => Thymus-dependent (T) lymphocytes or T cells => Thymocytes: developing T cells in thymus 2. Upper anterior thorax (above the heart). 3. Multiple lobules => Each has Outer Cortex => Dense T cells Inner Medulla => Sparse T cells Other cells: thymic epithelial cells (TECs), DCs, Macrophages => Cell-cell interactions and Cytokines

37. Thymus-II Positive selection Negative selection

38. T cell differentiation in the Thymus

39. 2nd Lymphoid Organ-Lymph Node (LN) LNs => Small nodular organ => Body => Lymphocyte activation Lymphocytes => Segregated in the distinct regions of LN The outer cortex => B cell zone (follicle) => Germinal Center (2nd follicle)=>B cell activation The inner region => T cell zone

40. Lymph Node (LN) Section

41. Lymph Node (LN) Section-II C => Cortex => B cell zone P => Paracortex => T cell zone M => Medulla

42. Spleen 1. The site of immune responses to blood Ags => A filter of blood 2. White pulp => T cell & B cell zones Marginal zone (MZ) Red pulp (RP) 3. T cells => periarteriolar lymphoid sheaths B cells => follicle => marginal zone

43. Mucosa-Associated Lymphoid Organs (MALT)

44. Outline Cells of the Immune System Anatomy & Functions of Lymphoid Tissues & Organs Summary & QuestionSummary & Question

45. SUMMARY 1. Immune cells are derived from “Bone Marrow (BM)”. T-lineage progenitor cells are first derived from BM and move to “Thymus” for maturation. 2. Key cells in innate immune responses include - Macrophage & DCs => Ag presentation - Granulocytes (PMNs) - NK cells 3. Key cells in Adaptive immune responses include - B lymphocytes => Ab => Extracellular bacteria - Several T cell types => Fight intracellular microbes & Regulate the program of an immune response 4. Primary lymphoid organs (BM & Thymus)=> Immune cell development 2nd lyphoid organs (LN & Spleen)=> Concentrate Ag from tissues or blood for lymphocyte activation.

46. Question What effect would you expect the thymus removal (thymectomy) to have on the ability of host immunity against infection?

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87. Overview of Lymphocyte Generation & Activation -I

88. Overview of Lymphocyte Generation & Activation -II

89. Activation of Lymphocytes In general, lymphocyte activation requires “Two Signals” (from Antigen presenting cells (APCs)) Signal 1: Ag  Ag receptor on lymphocytes (T & B) Signal 2: Molecules (innate response)  Costimulatory receptors on lymphocytes

90. Migration of Lymphocytes-I 1. In LN, naïve lymphocytes  HEVs Rolling => Adhesion => Transmigration Adhesion molecules for cell-cell interactions 2. In peripheral infection sites, effector lymphocytes  blood vessels

91. Migration of Lymphocytes-II