Natural Killer Cells

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Natural Killer Cells

• Teachers guide to natural killer cells

Lee-Hwa Tai Laboratory of Molecular
Immunology IRCM, Montreal, Canada
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What are Natural Killer cells?

• Natural killer (NK) cells are large, granular,
  bone marrow-derived lymphocytes of the innate
  immune system.
• NK cells DO NOT express T-cell antigen receptors
  or B cell surface immunoglobulins.
• NK cells DO express surface markers (ID badges)
  CD16 and CD56 in humans and NK1.1 in certain
  strains of mice.

NK cell
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What do NK cells do?

• NK cells are capable of recognizing and killing
  non-self cells (sick, infected, cancerous), while
  sparing normal healthy self-cells.
• While T cells can accomplish the same feats, they
  require a time consuming sequence of events that
  lead to their activation.
• NK cells are naturally primed to protect the
  body as a rapid response system until other arms
  of the immune system are mobilized.

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How do NK cells function?

• The cytolytic activity (killing ability) of NK
  cells must be tightly regulated.
• Regulation prevents the potential for
  auto-reactivity (killing own self, healthy
  cells).
• For NK cells to kill, they must receive an
  activating signal
• Cytokines (ex stress molecules released by
  virally infected cells)
• Fc receptors (receptors which bind antibodies
  that have covered and sequestered pathogen
  infected cells antibody dependent cellular
  cytotoxicity)
• Activating and Inhibitory receptors

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Activating and Inhibitory Receptors

• NK cells express germ line encoded cell surface
  receptors that recognize surface ligands on their
  targets (this is in contrast to the variant,
  somatically recombined T cell receptors).
• NK cells express both ACTIVATING and INHIBITORY
  cell surface receptors
• Binding of activating and inhibitory receptors
  results in downstream cell signalling events that
  lead to effector functions (kill or not kill)

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Where do NK cell receptors reside?
Nkrp1
Nkg2
Ly49
Families of NK receptors
Mouse chromosome. 6
Human chromosome 12
Natural Killer Gene Complex (NKC)
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What do NK cells recognize?

• Major Histocompability Class I (MHC class I)
  molecules are cell surface glycoproteins that
  present self and non-self peptides to both NK and
  T cells.
• All nucleated cells of the body express surface
  MHC class I molecules.
• MHC I self peptide healthy self cell
• MHC I pathogen derived peptide infected cell
• Viral MHC mimic virally infected cell

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"Missing Self" Hypothesis

• The term missing-self recognition is used to
  describe cells with low levels of MHC class I
  cell surface markers.
• This situation arises due to viral infection or
  the type of transformation that can occur in some
  types of cancer.

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NK Effector functions following Activation
Target Cell
Activating ligand
Activating receptor
KILL perforin granzymes cytokines

NK Cell
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Perforin

• Perforin is found exclusively in the cytoplasmic
  granules of mouse NK cells
• Pore forming protein of plasma membrane or
  endosome allowing granzymes to enter target cell
  cytoplasm
• Granulysin, which is found in humans is thought
  to function similarly to perforin
• Protease (enzyme that chews up proteins, kills
  cell) located in cytoplasmic granules of killer
  cells

Granzyme
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Effector functions following inhibition
Target Cell
MHC Class I
Inhibitory receptor
-
NK Cell
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A Balance of Inhibitory Stimulatory
SignalsRegulates NK Cell Recognition of Target
Cells
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Antibody Dependent Cellular Cytotoxicity
Target Cell
Ligand
Antibody
Fc receptor
KILL perforin granzymes cytokines

NK cell
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Conclusion

• NK cells are the first line of defense against
  virally infected and cancer transformed cells.
• Once activated through ligation of activating
  receptors, ligation of Fc receptors and cytokines
  secreted by distressed cells, NK cells unleash
  their arsenal of perforin and granzymes against
  target cells.
• It is the combination of signals received through
  activating and inhibitory receptors that
  ultimately determines the effector action of NK
  cells.

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