Functions of Th Cells, Th1 and Th2 Cells, Macrophages, Tc Cells, and NK Cells; Immunoregulation

1. Functions of Th Cells, Th1 and Th2 Cells, Macrophages, Tc Cells, and NK Cells; Immunoregulation

2. Antigen-presenting cell Ag Ag Tc cell Ag Th cell Cytokines B cell APC NK cell Macrophage Granulocyte NK Cytokines Critical Role of Th Cells in Specific Immunity • Select effector mechanisms • Induce proliferation in appropriate effectors • Enhance functional activities of effectors

3. Naive Th cells Short-term stimulation Long term Memory cells Chronic stimulation IFNγ IL-2 IL-12 ThM cell Th2 cell Th1 cell ThO cell ThP cell IL-4 IFNγ IL-2 IL-4 IL-5 IL-10 IL-2 IL-2 IL-4 IL-5 IL-6 IL-10 Naïve Th Cells Can Differentiate Into Th1 or Th2 Cells

4. Inhibits proliferation IL-10 Inhibits production Th1 cell Th2 cell IL-4 IL-5 IFNγ Activates Activates B cell Eosinophil Mast cell Macrophage Antibodies (including IgE) Functions of Th1 and Th2 Cells

5. Cytokines Regulate Ig Class Switching • Fc region of antibodies determines effector function in different anatomical locations • Class (isotype) switching produces class or subclass of antibody most effective in host defense • Cytokines acting alone or in combination regulate class switching

6. Th cell Invading agent Antigen presentation Activated macrophage Activate Macrophage Macrophage Macrophage Cytokines Anti-microbial functions Cytokines Lymphokines Anti-tumor functions Central Role of Macrophages in Natural and Specific Immunity • Involved in initial defense and antigen presentation and have effector functions

7. Detailed Functions of Macrophages Inflammation – Fever, Production of: IL-6, TNF-alpha, IL-1– act as pyrogen Damage to tissues Hydrolases, Hydrogen peroxide production Complement C3a TNF alpha production Immunity Selection of lymphocytes to be activated: IL-12 results in Th1 activation IL-4 results in Th2 activation Activation of lymphocytes: Production of IL-1 Processing and presentation of antigen Antimicrobial action O2–dependent production of: hydrogen peroxide, superoxide, hydroxyl radical, hypochlorous acid O2-independent production of: acid hydrolases, cationic proteins, lysozyme Anti-tumor activity produced by: Toxic factors Hydrogen peroxide Complement C3a Proteases, Arginase Nitric oxide TNF alpha Reorganization of tissues, Secretion of a variety of factors: Degradative enzymes(elastase, hyaluronidase, collagenase) Fibroblast stimulation factors Stimulation of angiogenesis

8. Macrophage Activation Macrophage activation results from alterations in gene products that govern new functions. Two major mechanisms that activate macrophages: • IFN-γ produced by Th or Th1 cells plus bacterial endotoxin (LPS) • IFN-γ produced by Th or Th1 cells plus TNF-α

9. 1 ActivatedMacrophage ActivatedMacrophage IFN gamma Bacterial endotoxin (lipopolysaccharide) triggers cytokine production Th1 cell TNF alpha IFN gamma Macrophage Macrophage Various products 2 Mechanism of Macrophage Activation

10. Cytolytic T (Tc) Cells • Tc exiting the thymus are pre-Tc cells, i.e. have TCR that can recognize antigen, but are not mature and cannot kill until “armed” • To become armed requires two signals: • Recognition by TCR of specific antigen associated with class I MHC, and • Exposure to cytokines (IL-2 and IFN-γ)

11. Class I MHC 1. Cell expressing class I MHC presents antigen ( )to a pre-Tc cell 2. Antigen-presenting cell presents antigen in association with class II MHC to Th cell 3. Th cell makes cytokines Pre-Tc cell T helper cell IFN IL-2 Class II MHC APC 4. Pre-Tc cell differentiates to functional Tc cell Tc cell 6. Target cell is killed 5. Tc recognizes antigen on class I MHC-expressing target cell Mechanism of Arming Tc Cells

12. Features of Tc Killing • Antigen-specific • Requires cell-cell contact • Each Tc capable of killing many target cells

13. Main Mechanism of Tc Killing • Tc granules contain perforin and granzymes • Upon contact with target cell, granule contents released, perforin polymerizes and forms channel in target cell membrane • Granzymes (serine proteases) enter target cell through channel, activate caspases and nucleases, lead to apoptosis of target cell

14. Mechanism of Tc Killing Tccell Tccell Granzymes Perforin monomers Perforin polymerizes Ca++ Polyperforinchannels Target cell Targetcell

15. Target cell 4. Target cell dies by apoptosis 2. A lethal hit is delivered by the Tc using agents such as perforin or granzyme B Tc cell Steps in Tc Killing 1. Tc recognizes antigen on target cell Tc cell Target cell Target cell 3. The Tc detaches from the target cell Tc cell Target cell

16. Natural Killer (NK) Cells • Derived from bone marrow • Lack most markers for T and B cells (do not haveTCR) • Do not undergo thymic maturation • Express CD56, a specific NK marker • Express a receptor for Fc portion of IgG, called FcRIII (CD16) • Cytokines (IL-2) promote differentiation into lymphokine-activated killer (LAK) cells

17. NK Cell Effector Mechanisms • Mechanism of killing similar to those of Tc cells • Not MHC-restricted • Susceptibility of target cell to killing is inversely proportional to expression of class I MHC (killer inhibitory receptors (KIR) on NK cells recognize class I MHC and prevent killing)

18. NK Effector Mechanisms(continued) • IgG-coated target cells recognized by FcRIII (CD16) are killed by antibody-dependent cell-mediated cytotoxicity (ADCC) • Lymphokine-activated killer cells (LAK) kill broader range of cells than do NK cells

19. Regulation of Immune Responses • Magnitude determined by balance between the extent of lymphocyte activation and tolerance induced by an antigen • Nature determined by specificities and functional classes of lymphocytes activated • Regulatory mechanisms may act at the recognition, activation, or effector phases of an immune response