Natural Born Killers

Question 1

What are the origins of NK and T cells?

Answer 1

Both arise from common lymphoid progenitor cell
Both part of the lymphocyte lineage
Natural killer cells are a subset of innate lymphoid cells

Question 2

What is the role of cytotoxic lymphocytes?

Answer 2

We need cytotoxic cells to be able to destroy:
- Cells infected with bacteria, viruses or parasites
- Tumour cells
Lymphocytes scanning a target cell surface need to detect changes in protein production inside that target cell
CD8 are controlled by T cell receptor recognition, with CD8 acting as a co-receptor
- CD8 receptor attaches to its target antigens and helps stabilise it
Highly specific

Question 3

Why do we need more than one type of cytotoxic lymphocyte?

Answer 3

1. To combat infection in the period before a T cell response develops
   
   2. To provide an alternative system when a tumour or infected cells evade Cytotoxic T cell responses
   3. To provide an additional mechanism for killing infected targets via antibody recognition

Question 4

How are peptides presented on MHC class I?

Answer 4

Proteins expressed within a cell are processed and presented on MHC class I proteins
Samples include ‘normal’, mutated or viral proteins
These proteins enter a protease complex called the proteosome which chops them up into smaller peptide fragments
These peptide fragments then enter the endoplasmic reticulum which is where they come into contact with empty MHC class I
If a peptide fragment binds MHC class I then the whole complex starts to exit towards the cell surface where the MHC class I hold out the peptide for a T cell to see it

Question 5

What is the structure of MHC class I?

Answer 5

Tissue distribution: found on all nucleated cells
It has peptide binding cleft made of two alpha helices and a beta pleated sheet forming a base
There is also an alpha chain and beta2-microglobulin supporting the cleft
two polypeptides, non-covalently bound

Question 6

Why do we have HLA polymorphism?

Answer 6

Pathogens can evolve to evade immune responses
Variation in MHC class I proteins - Multiple genes (e.g. two copies each of HLA-A, B and C) and high genetic variability within these genes may counteract this across populations

Question 7

What do TCRs recognise in MHC?

Answer 7

MHC-I proteins play a central role in the ability of the immune system to distinguish self from non-self
T Cell Receptors (TCR) recognise two things
- MHC protein itself (hence compatibility…)
- Antigenic peptide presented by MHC protein

Question 8

How does TCR bind to MHC?

Answer 8

CD8 acts as a co-receptor for MHC-I, and is required for the T cell to make an effective response
TCR binds to the a1a2 domains
CD8 binds to the support domains (a3 and b2m)

Question 9

How can pathogens subvert presentation by MHC-I?

Answer 9

Inhibit MHC-I transcription (adenovirus)
Block peptide transport into the endoplasmic reticulum (HSV)
Retain MHC-I in endoplasmic reticulum (adenovirus, HCMV)
Target MHC-I for disposal from the endoplasmic reticulum (HCMV)
Downregulate MHC-I from cell surface (HIV)

Question 10

What is the function of Killer Ig-like receptor?

Answer 10

When KIR recognise MHC-I they inhibit NK cells from releasing lytic granules
Some viruses down-regulate MHC-I as a means to evade cytotoxic T cells, loss of MHC-I is also a common feature of tumour cells
If a target cell does not express MHC-I then there is no KIR inhibition, lytic granules will be released to lyse the target
This mechanism is known as “missing self”

Question 11

What are the characteristics of KIR?

Answer 11

Inhibitory KIR bind to the same face of MHC-I as the T cell receptor
recognise subsets of MHC-I alleles
KIR are also polymorphic, as well as being polymorphic individual KIR genes vary in their presence between individuals
Different MHC-I/KIR combinations show disease associations e.g. in HIV infection

Question 12

What do natural cytotoxicity receptors do?

Answer 12

These provide activating signals to NK cells, but their range of ligands are not well characterised
NKp46 is known to bind viral hemagglutinin
NKp44 – binds a ligand that is expressed on tumour cells and upregulated by viral infection
Ligand for NKp30 is a stress induced protein

Question 13

Why do NK cells kill tumour cells?

Answer 13

Similar to many pathogens, tumor cells can escape the adaptive immune system, by downregulating the expression of MHC class I.
This makes them more susceptible to NK cells.

Question 14

What is ADCC?

Answer 14

Antibody-dependent cell-mediated cytotoxicity (ADCC)
NK cells express a receptor that recognizes the Fc portion of antibodies
This receptor delivers a strong activating signal when it recognizes antibodies bound to a cell surface
Results in lysis of the target cell

Question 15

What cytotoxic granules do to cells?

Answer 15

NK cells and T cells carry granules filled with cytotoxic proteins
Release cytotoxic granules at site of contact with target cell
(must be directed in order to avoid damaging innocent bystander cells)
Some of the proteins:
- Perforin- Punches holes in the membrane and aids in delivering contents of granules into the cytoplasm of the target cell
- Granzymes- these are serine proteases, which activate apoptosis once in the cytoplasm of the target cell
- Granulysin- Has antimicrobial actions and can induce apoptosis

Question 16

How do CD8 cells trigger apoptosis?

Answer 16

CD8 cells can also trigger apoptosis of target through Fas/FasL interaction
This process is slower than cytotoxic granules (2 hour lag time)
Fas ligand (FasL) on T cells engages Fas on target cells to trigger apoptotic pathway
Fas/FasL triggered apoptosis is used to dispose of unwanted lymphocytes
Loss of Fas can result in autoimmune lymphoproliferative syndrome (ALPS)