Immunology Chapter 6

==NK cells Characteristics==

• made in bone marrow from common lymphoid progenitor
• circulate blood and move into tissue during inflammation
• larger than other lymphocytes (B and T cells)
• contains granules like T cells
• mechanism of killing is like CTL → release proteins from granules which enter target cell and signal it for apoptosis
• known to kill certain tumor cells and are important in immunity to intracellular pathogens including viruses

==NK cells Activation==

• Interferon:
  • @@type I interferon@@ = IFNα and IFNβ = produced by cells in response to viral infection
  • @@type II interferon@@ = IFNγ → doesn’t activate NK cells
  • dsRNA binds to TLR-3 = makes IFNα and IFNβ
  • all secreted by infected cell
• Functions of interferons:
  • type I interferons binds to interferon receptor on infected cell & neighboring cell = anti-viral state
  • (look at slide 4)
• Activation of NK cells:
  • binding of type I interferons to interferon receptors on NK cells stimulates increased expression of IL-12 receptors

^^IL-12^^

• produced by macrophage during infection
• activates NK cells, stimulating production of IFNγ
• effects of IL-12 are increased when NK cells are exposed to TNFα, or IL-18, or IL-1β at the same time as IL-12
  • these cytokines are activated by macrophages

^^IL-15^^

• NK cell growth factor
• produced by macrophages during infection
• knockout mice that cannot make IL-15 or its receptor produce very few NK cells

^^IL-2^^

• high concentrations of IL-2 increase the killing ability of NK cells
• produced by T helper cells

==Functions of NK cells==

@@1.) Production of cytokines@@

• activated NK cells and secrete large amounts of IFNγ
• IFNγ activates macrophage
• macrophage must be activated by respiratory burst and make nitric oxide → activated macrophage are good at killing organisms brought in by phagocytosis or intracellular pathogens
• activated macrophages produce and secrete more IL-12 than before activated
• activated NK cells produce $TNFα$ (promotes inflammation and activates macrophages, $GM-CSF$ (produces granulocytes and macrophages), and chemokines MIP1α & MIP1β (recruit and activate macrophages)

@@2.) Antibody Dependent Cell Cytotoxicity (ADCC)@@

• cells infected with viruses or intracellular bacteria expresses viral or bacterial proteins on surface
• antibodies against these proteins can bind to cells
• NK cells express $FcγRIII$ (CD16) → receptor for Fc region of IgG
• more than one IgG bound to surface binds to FcγRIII on NK cells = triggers NK cell to kill cell

@@3.) Cytotoxicity (cell killing)@@

$$A.) release enzymes from granules by CTLs$$

• degranulation = granules move to surface of cell where granule membrane fuses with cell membrane releasing granule contents
• perforin = protein released during degranulation
  • binds to target cells and transports granzyme into cell
• presence of granzyme inside cell is a signal to the cell that it should undergo apoptosis

$$B.) activation of apoptosis without degranulation$$

• NK cells produces TRAIL (protein)
• TRAIL binds to DR4 & DR5 = DR4 & CR5 cluster
• inside cell to be killed, FADD binds to clustered DR4 & DR5 = active
• active FADD cleaves pro-caspase 8 into active caspase 8 = starts apoptosis

==Control of NK Cell Killing==

@@1.) cytotoxicity activating receptors bind to ligands@@

• send signal inside NK cell that starts killing process

@@2.) cytotoxicity inhibitory receptors bind to ligand@@

• inhibitory receptors bind to class I MHC
• no killing

@@3.) infected cell and tumor cell have altered expression of class I MHC@@

• class I MHC = signals to not kill cell

@@4.) NK cells kill cells that have changed due to stress@@

• NKG2D = activating receptor
• binds to MIC-A, MIC-B, or RAET1
• stress = infection with intracellular bacteria, infection with virus, DNA damage, or transformation to malignant tumor cells
• NKG2D binds to ligand = activates killing

@@5.) Innate Lymphoid Cells (ILCs)@@

• NK cells are a type of ILC
• non NK cell ILC does not kill other cells like NK cells
• ILC produced through hematopoiesis from common lymphoid progenitor
• bone marrow → bloodstream → lymphoid tissue → dermis, liver, small intestine and lungs
• ILC1 = fighting viral & intracellular infections
• ILC2 = fighting parasites
• ILC3 = fighting extracellular bacteria & fungi