Lec 13 Cell-mediated effector responses PDF

Cell-mediated effector responses 1 Cellular effector responses Microorganisms replicating in the cytoplasm: cytolytic responses Phagocytosed microorganisms: T-cell-mediated activation of phagocytes Helminthic infections: ADCC and IgE-mediated activation of eosinophils 2 Th-cell differentia...

Cell-mediated effector responses 1 Cellular effector responses Microorganisms replicating in the cytoplasm: cytolytic responses Phagocytosed microorganisms: T-cell-mediated activation of phagocytes Helminthic infections: ADCC and IgE-mediated activation of eosinophils 2 Th-cell differentiation • Helper T cells can be divided into distinct subsets – At least five distinct subsets • • • • TH1 and TH2 TH17 TREG TFH – Each produces a distinct cytokine profile and regulates distinct activities within the body 4 Cytolytic responses • CTL (CD8+) cells recognize foreign antigens presented on MHC class I molecules with their specific TCRs • NK cells recognize altered self-cells by activating and inhibitory receptors 5 Requirements for CTL activation • Ag recognition: TCR • Co-stimulation: CD28/B7 • IL-2: proliferation 6 Destruction of target cells by CTL 7 Cell-mediated effector responses • CTLS recognize and kill infected or tumor cells via TCR activation – How CTLs kill cells • Perforin/granzyme pathways • Fas/FasL pathways 8 Events in the destruction of target cells by CTL • Conjugate formation • Membrane attack • CTL dissociation • Target cell destruction 9 Destruction of target cells by CTL https://www.youtube.com/watch?v=ntk8XsxVDi0 10 Conjugate formation • TCR/CD3 complex interacts with MHC/Ag • LFA-1 integrin receptor binds to ICAM • LFA-1 acquires a high avidity for its ligand after Ag recognition (only for 5-10 min) 11 Reorientation of CTL cytoplasmic granules • CTL have intracellular storage granules containing granzymes (proteases) and perforins (pore-forming proteins) • After conjugate formation granules reorient within the cytoplasm near the junction with target cell 12 13 Cell-mediated pore formation 14 Perforin-mediated cell lysis • Perforin-mediated pore formation facilitates entry of granzymes. • Proteolytic activity of granzymes activates an apoptotic pathway which leads to DNA fragmentation • This process does not require mRNA or protein synthesis (5 min enough to detect DNA fragmentation) • It not only destroys infected cells but also viral DNA • Additional killing mechanisms include Fas/FasL and TNF 15 Fas-mediated cell lysis 16 Mechanisms of target cell killing by CTL 17 Cell killing mediated by NK cells • NK cells lyse infected cells which do not express MHC class I molecules. • NK cell activation is regulated by a balance between inhibitory and activating receptors • NK cell activity is also modulated by cytokines, mainly IL12 and IL-15 • Earlier than T-cell response 18 Cell killing mediated by NK cells • NK cells use similar mechanisms to kill target cells 19 Inhibitory and activating receptors in NK cells 20 NK cell functions Direct clearance of infected cells Indirect clearance of pathogens through macrophage activation 21 Antibody-dependent effector functions 22 Antibody-dependent cell-mediated cytotoxicity (ADCC) • Some cells with cytotoxic potential express FcR→Upon antibody recognition they are activated and kill Agexpressing target cells • Non-Ag specific cells, specificity is given by the antibody • Mechanism used by NK cells, macrophages, neutrophils and eosinophils • Useful to eliminate virus (macrophages), helminths (eosinophils) and other pathogens • Different lytic mechanisms: lytic enzymes, TNF, perforin, 23 granzymes Antibody-dependent cell-mediated cytotoxicity (ADCC) 24 Killing of intracellular pathogens 25 Phagocytosis and killing of intracellular pathogens 26 Summary • Cellular effector responses contribute to pathogen clearance through direct killing by CTL or NK cells • Antibodies may also collaborate as bridges with cellular responses • Macrophages eliminate intracellular pathogens once activated by T cells 27