Natural Killer cells

Introduction

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 are able to down-regulate MHC expression of the infected cell; this mechanism is also used as a protection against the host immune system as a lack of MHC inhibits normal T-cell activity. NK cells can counteract the down-regulation tactic and in this regard 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 because although they trigger functional activity within the cell, they do not stimulate proliferation and there is no clonal expansion of NK cells. NK cells work through two different types of receptors:

1. Activating receptors, R1 which recognise pathogen-associated glycolipids or Fc receptors (E.g. CD16 recognises Ig that is bound to pathogen antigens)
2. Suppressing receptors, R2 which 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 NK cells.

If the target cell does not express MHC, the suppressing receptors are not engaged; the engagement of R1 therefore causes activation of the NK cells

Activated NK cell Response

NK cells secrete a range of cytokines, including:

• Tumour necrosis factor alpha; (TNFα) - a potent stimulator of acute inflammation which can cause target cell killing directly and also via stimulated macrophages.
• Interferon gamma; (IFNγ) which stimulates macrophages to be active against the target cell and stimulates target cell expression of MHC.

Originally funded by the RVC Jim Bee Award 2007

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