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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

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
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

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

slide7

Target

M

  • Resting macrophages are not lytic
  • Activated macrophages (courtesy of Th1 cells) are lytic

2 signals required: Interferon- (IFN-)

CD40L

Target

M

mechanisms of macrophage mediated cytotoxicity
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
slide9
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
activation of cytotoxic t lymphocytes
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

ctl activation
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
characteristics of effector ctl
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
molecules important for cd8 t cell cytotoxicity
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
mechanism of ctl mediated killing of targets
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

other important roles of fas fasl
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
supramolecular activation cluster smac

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

natural killer cells
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

natural cytotoxicity receptors

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

nk cell receptors
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

beneficial and deleterious effects of cytotoxicity
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
suggested reading
Suggested Reading
  • Immunobiology: The Immune System in Health and Disease by Janeway et al. 6th ed., 2005. Pg 89-95; 341-361;717.