Natural Killer cells

(NK)

Healthy cells present MHC to NK cells to suppress their activation - B. Catchpole, RVC 2008

Infected cells lack MHC, which means they cannot switch off the NK activation signal - B. Catchpole, RVC 2008

Natural Killer cells release enzymes to kill cells with inadequate MHC presentation - B. Catchpole, RVC 2008

Infected cells are destroyed before replication - B. Catchpole, RVC 2008

NK cells can be classified as lymphocytes because they are capable of recognising antigen, however they are more often associated with the innate immune response. They target cells by monitoring MHC production, which is expressed by healthy cells to present antigen to T-cells. Low MHC levels can be used as a marker for a cell whose machinery is compromised by a replicating virus. When MHC levels drop, it acts as a danger signal to the NK cells, which then release enzymes to kill the infected cells.

NK cells do not develop in the thymus and represent 5-10% of the circulating lymphocytes. They recognise and kill transformed cells by releasing perforins and granzymes which create channels in the target cell membrane causing lysis. They express the markers CD16, CD56 and CD94.

Natural Killer cells also play a role in Antibody-Dependent Cell-mediated Cytotoxicity

NK Receptors

• Some viruses down-regulate MHC expression of the infected cell
  • This is used as a protection against the host immune system
    • Lack of MHC inhibits normal T-cell activity
• NK cells can counteract the down-regulation tactic
  • They are mainly associated with activity against virus-infected cells and tumour cells, which can also have lowered MHC expression
• The receptors on NK cells do not act like antigen-specific receptors
  • Although they trigger functional activity of the cell, they do not stimulate proliferation
    • There is no clonal expansion of NK cells
• NK cells work through two different types of receptors
  • Activating receptors, R1
    • Recognise pathogen-associated glycolipids or Fc receptors
      • E.g. CD16 recognises Ig that is bound to pathogen antigens
  • Suppressing receptors, R2
    • Recognise target cell MHC molecules
• When an NK cell interacts with a target cell it will be activated via R1
  • If the target cell expresses MHC this will be seen by R2
    • R2 suppresses the activities of the NK cells
      • Therefore, NK cells do not affect normal cells
  • If the target cell does not express MHC, the suppressing receptors are not engaged
    • Cell activity is not suppressed
      • The engagement of R1 therefore causes activation of the NK cells

When NK cells are activated, they:

• Secrete a range of cytokines, including:
  • Tumour necrosis factor alpha; (TNFα)
    • A potent stimulator of acute inflammation
    • Can cause target cell killing directly and also via stimulated macrophages
  • Interferon gamma; (IFNγ)
    • Stimulates macrophages
    • Active against the target cells
      • Stimulates target cell expression of MHC
      • Makes target cells susceptible to normal T-cell killing.
• Initiate killing of the target cell