Natural Killer Cells

Natural Killer Cells

1. Made in the bone marrow

   • Stem cell to NK Cell (IL-21)
   • Secondary Lymphoid Organs
     • CD3+, CD56+ NKp46+ NK cell
     • CD56
     • IL-15
       • Dendritic cell help

2. Receptors

   • IL-18R
     • Required for Stimulation
   • IL-12R
   • CD56
     • (NCAM-1)
   • CD16
     • (FcγRIIIa)
       • receptor for IgG1 and IgG3
   • KIR
     • Inhibiting
       • Intracellular ITIMS (stop signalling)
         • HLA receptor
     • Activating
       • Intracellular ITAMS (phosphorylated to initiate signalling)
   • Natural Cytotoxicity Receptors
     • Nkp30
     • NKp46
       • Selective marker for NK cells

3. Activation

   • IFNα & IFNβ
   • IL-18 & IL-12
     • APC
   • Imbalance between activating and inhibiting signals
   • Fc receptor engaged
   • Prodcution of IFNγ
     • Stimulates macrophage effector functions
   • Granule release
     • Induces apoptosis of target
   • Activation of death ligands

4. Effector Functions

   • Induce apoptosis of target cell
     • Attach to a cell (immunological synapse)
       • Granule polarisation
         • LFA-1
         • ICAM-1
         • Release of granular contents into synapse
           • CD16 activation
           • Perforin
             • Forms pores in target cell membrane
           • Granzymes
             • 5 different kinds in humans
               • A
                 • Causes nicks in DNA
                   • Activates TREX1
                     • Stops DNA repair
               • B
                 • Activates Caspase cascade
                   • Caspase 3 & 7
                   • Acts on mitochondria
                     • Forms apoptosome
                 • Can enter via Mannose-6-phosphate too
               • C
               • K
               • M
           • Granulysin
             • Contains antimicrobial peptides
     • Intrinsic pathway
       • Mitochrondria mediated
     • Extrinsic pathway
       • TRAIL on NK:DR4/DR5
         • FADD
       • TNF-α from NK:TNFR1
         • TRADD