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