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Cytotoxicity in health and disease

Cytotoxicity in health and disease. Ronald B. Smeltz Dept. of Microbiology and Immunology Medical Sciences Building Room 323/325 Tel. # 828-8085. Cytotoxicity = Cell killing or lysis. Effectors Complement (C’) Macrophages (M  ) Granulocytes (neutrophils, eosinophils)

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Cytotoxicity in health and disease

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  1. Cytotoxicity in health and disease Ronald B. Smeltz Dept. of Microbiology and Immunology Medical Sciences Building Room 323/325 Tel. # 828-8085

  2. Cytotoxicity = Cell killing or lysis Effectors • Complement (C’) • Macrophages (M) • Granulocytes (neutrophils, eosinophils) • Natural Killer (NK) cells • Cytotoxic T lymphocytes (CTL) Ag Ab C’ Classical pathway

  3. Cells targeted for killing • Tumors • Virally infected cells (HSV, CMV) • Cells infected with intracellular bacteria (Listeria, Chlamydia) • Intracellular protozoa (Trypanosoma, Plasmodium) • Allografts (MHC mismatch)

  4. Complement • Classical, alternative, and lectin pathways • IgM, IgG (IgG4<IgG2<IgG1<IgG3) • Membrane attack complex (MAC) forms a pore and lyses target cell • Result is necrotic cell death • Lysis critical for removal of immune complexes • C5,C6,C7,C8,C9-/-: absent lytic activity meningococcal infections

  5. Macrophages • Monocyte (blood)- tissue macrophage precursor • Alveolar macrophagess–lung • Histiocytes – connective tissue • Kupffer cells – liver • Mesangial cells – kidney • Microglial cells – brain • Splenic macrophages localized to red/white pulp areas

  6. Function of macrophages • Phagocytosis • Antigen processing and presentation, bridge to adaptive immunity • Cytotoxicity • Direct cytotoxicity • Antibody dependent cell-mediated cytotoxicity (ADCC) Target Ag M Ab Fc receptor

  7. Target M • Resting macrophages are not lytic • Activated macrophages (courtesy of Th1 cells) are lytic 2 signals required: Interferon- (IFN-) CD40L Target M

  8. Mechanisms of macrophage-mediated cytotoxicity • Reactive oxygen intermediates (ROIs): O2-, OH-, H2O2 • Reactive nitrogen intermediates (RNIs): NO, NO2 • Tumor necrosis factor- • Lysosomal enzymes • Result is necrotic death

  9. ADCC • Requires pre-formed antibody bound to specific antigen • Secondary immune response (adaptive immunity/B cells) • Maternal IgG • IgG1, IgG3 (humans) • Requires cross-linking of FcRIII-receptor (CD32/16) on effector cell (including NK cell) • Result is apoptosis of target cell

  10. Activation of Cytotoxic T lymphocytes IL-2 IL-2R CTL Precursor Ag Activated CTL MHC Class I CD8 Target TCR Ag Proliferation, Differentiation Activation Intracellular antigens

  11. CTL Activation • Ag + Class I MHC on infected cells/grafts CTL • Ag + Dendritic cells (Class I) – cross priming of naïve CD8+ cells • Ag + APC + CD4+ Th CTL

  12. Characteristics of Effector CTL • Increased adhesion molecule expression (LFA-1, CD2, CD44, CD45RO) • Decreased expression of CD62L (L-selectin) (permits exit from lymph nodes) • Expression of VLA-4 (Very Late Ag-4) which interacts with VCAM-1 (vascular cell adhesion molecule) on endothelial cells leading to inflammation • Production of effector lytic molecules

  13. Molecules important for CD8+ T cell cytotoxicity • KLR (Killer cell lectin-like receptor): CD94, NKG2 • Bind to MICA, MICB (human) • Bind to Rae (mouse) • Act as co-stimulatory molecules for primed CD8+ T cells

  14. Mechanism of CTL-mediated killing of targets Pathways • FasL (contact-dependent) • Perforin/Granzyme (contact-dependent) • Cytokines: IFN-g, TNF-a and TNF-b Perforin TCR Ag CTL MHC Granzyme Fas FasL Perforin

  15. Other important roles of Fas/FasL • Homeostasis: • Limiting of the immune response • Mice deficient in either Fas/FasL develop lymphoproliferative disorders • Mice deficient in perforin unable to limit CD8+ T cell responses

  16. Immunologic Synapse between CTL and target cell Supramolecular Activation Cluster (SMAC) cSMAC (central) MHCp:TCR CD28:CD80/CD86 Exocytic vesicles pSMAC (Peripheral) LFA-1:ICAM-1 Microtubules Outside of SMAC CD43/CD45

  17. Natural Killer Cells • Large granular lymphocytes • Kill virus infected cells and tumor cells • Lysis non-MHC restricted, but contact-dependent • CD3-, TCR-, Ig-, typically CD56+ • Present in SCID (severe combined immunodeficiency disease) mice • Intermediate affinity IL-2R+ • FcR(CD16)+, Mediate ADCC • Deficiency: increased susceptibility to Herpesviridae

  18. ITIM ITIM Natural Cytotoxicity Receptors Altered-self hypothesis • Activating Receptor: Contain immunoreceptor tyrosine-based activation motif (ITAM) • Inhibitory Receptor: Contain Immunoreceptor tyrosine-based inhibitory motif (ITIM) ITAM

  19. NK Cell Receptors • KLR (Killer cell lectin-like receptor): CD94, NKG2 • KIR (Killer cell Ig-like receptor): Ly49 Human: NKG2A and B are inhibitory NKG2C and D are activating Mouse: Ly49H is activating Other Ly49 is inhibitory Recognize: Nonclassical MHC: HLA-E – human; Qa-1 – mouse (Classical MHC : HLA-A,B,C,D –human H-2K,I,D – mouse

  20. Beneficial and deleterious effects of cytotoxicity • Protection against • Tumors • Virus-infected cells • Intracellular bacteria • Parasites • Fungal infections • Cause • Autoimmune disorders (Type 1 diabetes) • Transplant rejection (including spontaneous abortion) • Immunopathology

  21. Suggested Reading • Immunobiology: The Immune System in Health and Disease by Janeway et al. 6th ed., 2005. Pg 89-95; 341-361;717.

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