NK Cells

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NK cells

• Lymphocytes
  • Part of the ILC family of cells
  • Development requires expression of Id2, Nfil3 and Eomesodermin (Eomes)
  • Presence of IL-15
  • Lack Ag-specific receptors
  • Not many receptor are uniquely expressed by NK cell
  • Most commonly used combination is CD56+ and CD3-
    • CD56 is present on some differentiated T cells
    • Only works in human
• Functions
  • Lyse target cells
    • Perforin/Granzymes dependent
      • Releases cytotoxic granules
    • TRAIL
      • TNF related apoptosis inducing ligand
      • Interactions with DR4 and DR5 - death receptors
    • Engagement of DR4/DR5
      • Activates caspase 8 leading to apoptosis
    • Key roles in immunity to viral infections and tumour
    • Emerging role in reproduction
      • NK cells activation may promote remodelling/widening of spiral arteries which provide nutrient to the placenta
  • Secrete cytokines
    • IFN-gamma ; TNF-alpha
  • Secrete chemokine
    • XCL1
• Activation
  • Cytokines
    • Type I interferons, IL-2, IL-15, IL-18
  • Cellular interactions
    • Antibodies dependent cellular cytotoxicity
      • CD16 (FcyRIII)
        • Associate with CD3 like adaptor that contains ITAMs
      • Require antibody
        • Adaptive immune response
    • Natural cytotoxicity
      • Role of MHC class I and MHC class I like proteins
        • “Normal” cells express class I not liked by NK cells
        • Inhibitory receptor bind to MHC I (prevent activation of NK cells)
        • Virus infections (HSV, CMV) can downregulate MHC class I expression increase susceptibility to NK cells lysis
        • Tumor cells frequently have defective class I expression - increase susceptibility to NK cell lysis
        • Complement CD8 T cell recognition of MHC I
      • Role of MHC class I and MHC class I like proteins
      • Adhesion molecules (CD2, 2B4)
      • Natural cytotoxicity receptors (NKp30, NKp44, NKp460
      • Activating forms of CD158/Ly49
      • NKG2D
        • Expressed by all NK and certain T cell subsets
        • Potent activation - costimulation of T cells
        • Ligands:
          • MIC-A/B and ULBP in human
            • Tightly regulates expression
              • Non constitutive
                • Low or absent in most adult tissues
              • Inducible
                • Heat shock
                • Viral infection (CMV)
                • Bacterial infection TB
                • Pathogenic E.coli
              • Frequently expressed on tumour/transformer cells
            • Expression of NKG2D ligands indicated cellular stress - infected/transformed cells
              • Initiated by protein kinase ATM or ATR
              • Induced as result of DNA damage
                • Cleaved dsDNA
                • Stalled replication forks
          • RAE-1 and H60 in mice
        • MHC class I-like molecule
  • Control by balance
    • Activated by increasing activation receptor
      • FcR, NKG2D
    • Activated by decreasing in inhibitory receptor
      • KIR, NKG2A, Ly49, LILR
• Inhibition
  • Ly49 receptor
    • Expressed by rodent NK cells
    • Member of the C-type lectin superfamily
    • Recognise H-2K and H-2D class I molecules
  • NKG2A/CD94
    • Expressed by both rodent and primate NK cells
    • Members of the C-type lectin superfamily
    • Recognise non classical MHC I molecules
      • Ubiquitous expression not polymorphic
      • CD94-NKG2A recognise MHC I derived signal sequence peptide presented by HLA-E
  • Killer cell Ig-like receptor KIR-CD158
    • Expressed by primate NK cells
    • Member of the Ig-superfamily
    • Recognise groups of HLA-A, B, C allotypes
      • Inhibitory receptors signals via Ig tyrosine-based inhibitory Motif (ITIM)
      • Recognise 4 epitopes present on group of class I molecules
        • These epitopes are mutually exculsive
        • Some HLA alleles will posses none of these determinant
      • KIR use the inter domain ‘elbow’ regions to bind to HLA
      • KIR bind over the C-terminal region of the peptides
      • KIR and TCR have practically overlapping footprint on HLA class I molecules
      • Interaction between KIR and self-MHC regulate “responsiveness”
        • Unlicensed cells can response during acute viral infraction role for pro-inflammatory cytokines
  • NK cells with an individual can express different inhibitory receptor