NK Cells

Question 1

What are NK cells?

Answer 1

Natural killer (NK) cells are part of the innate immune system (they are not antigen specific). They make up 5–15 % of peripheral blood leukocytes and a greater percent of resident leukocytes in certain tissues such as the liver.

Unlike B and T lymphocytes, NK cells do not express somatically rearranged receptors, but rather possess a variety of germline-encoded receptors.

NK cells are capable of recognising cells that are transformed (cancers) or infected with pathogens and kill these cells via the release of cytotoxic granules or through death receptors.

NK cells secrete cytokines such as IFN-gamma, which is pivotal in fighting infection and in shaping the developing immune response .

NK cell activity is controlled by signals derived from activating and inhibitory receptors.

In general, activating receptors recruit kinases through associated ITAM-containing proteins whereas the inhibitory receptors recruit phosphatases through the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) located in their long cytoplasmic tails.

Question 2

Innate Lymphoid Cells:

Answer 2

Critical for homeostasis, early response to pathogens and amplification of CD4+ Th adaptive immune response.

Reside in periphery (especially mucosa) as opposed to T cells which mainly reside in lymphatics/LN`(Lymph Nodes)/spleen.

ILCs are very rare, <1% of lymphocytes in mucosa.

Question 3

The Missing Self Hypothesis:

Answer 3

Integration of all the inhibitory and activating signals determines whether the NK cells will kill or spare the target cells.

The inhibitory receptors mostly interact with MHC class I ligands that normally present peptide antigens to CD8+ cytotoxic T cells

Thus, cells evading recognition by CD8+ T cells through down-regulation of MHC class I proteins might become susceptible to NK cell-induced cytolysis.

(i.e. Loss of MHC molecule expression induces killing)
This is known as the ‘‘missing-self hypothesis’’.

Question 4

Cytotoxic T Lymphocytes (CTLs) vs NK Cells:

Answer 4

CTLs
CTLs recognise foreign proteins on class I MHC
All nucleated cells express class I MHC (except neurons)
Class I MHC presents “endogenous antigens”
(i.e. those from inside the cell)
Kill the infected cell

NK cells
CTLs recognise antigen presented on MHC Class I.
Many pathogens (esp. viruses) and tumours downregulate expression of MHC I.
NK cells recognise downregulation of MHC Class I, and kill the cell (missing self)
Can also recognise “stress” molecules, indicating infection (upregulation of stress induced ligands promotes killing)
NK cells kill using perforin/granzyme or FASL, like CTLs

Question 5

Inhibitory and activating receptors of NK cells:

Answer 5

Inhibitory receptors bind MHC class I
Activating receptors bind “stress ligands”

Under normal conditions:
Inhibitory signal outweighs activating signal.
NK cell inhibition (= “don’t kill”)

Some pathogens (eg viruses) and tumours downregulate MHC class I to avoid CD8+ CTL killing
So the NK cell gets a weaker inhibitory signal
“Missing self”
Activating signals outweigh inhibitory signals
NK cell activation (= “kill!”)

Even if the tumour/virus doesn’t downregulate class I MHC, infected cells produce more stress molecules
“Stress-induced self”
Activating signals outweigh inhibitory signals
NK cell activation (= “kill!”)

Question 6

NK cell killing machinery:

Answer 6

Granules containing perforin and granzymes

Perforin creates holes in plasma membrane of target cells (a bit like the complement membrane attack complex)

Granzymes are serine proteases stored in NK cell granules and released on NK activation and enter target cells via perforin-induced pores.

Activation of caspases induces target cell death

FasL on NK surface induces apoptotic cell death via interactions with Fas ‘death receptor’ on target cells.