Natural Born Killers: NK Cells And CD8+ T Lymphocytes

Question 1

What is the origin of natural killer cells and T cells?

Answer 1

Both arise from Mormon lymphoid progenitor cells

Both part of lymphocytes lineage

Question 2

What is the role cytotoxic lymphocytes?

Answer 2

We need cytotoxic cells to be able to destroy cells infected with pathogen and tumour cells

Lymphocytes scanning a target cell surface to detect changes in protein production inside that target cell

Question 3

What are natural killer cells and what is they’re function?

Answer 3

Cytotoxi INNATE immune cells

Kill virally infected targets

Kill tumour cells

Controlled by a balance of signals between activating/inhibitory receptors on their surface

Broad specificity for target cells

Question 4

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

Answer 4

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

Question 5

what is the correlation between NK cells and infection?

Answer 5

Low NK cell activity results in servere disseminating herpesvirus infections

Question 6

What is the role of MHC 1?

Answer 6

MHC 1 proteins are found on th cell surface

They for a a structure that presents protein frangment at the cell surfaces or immune survallience

ALLOW A WAY FOR OTHER CELLS TO NOW WHATS HAPPENING INSIDE A CELL

Recognised by CD8+ cytotoxic T cells

Question 7

How are intracellular proteins presented at the cell surface by MHC1?

Answer 7

Proteins are processed and presented on MHC1 proteins

1. Proteins enter proteasome
2. Proteasome breaks down protein into smaller peptide fragments
3. Fragments enter the endoplasmic reticulum
4. Fragments bind with MHC class 1 in the endoplasmic reticulum
5. After binding the of complex migrates to the cell surface where it is presented

Question 8

Describe the structure of MHC1

Answer 8

2 polypeptides not covalently bound

Peptide binding cleft at the top
- where short peptide fragment bind
— 2 alpha helixes with Beta pleated sheet between them
- amino acids form binding groves to relate pockets for where bound peptides can anchor

Beta2 micro globulin - forms lower structure

FOUND ON ALL NUCLEATED CELLS

Question 9

where is the MHC gene complex located?

Answer 9

Chromosome 6

3 MHC class 1 Proteins

3 MHC class 2 proteins

Highly polymorphic - 100s of different genetic variants

Question 10

What are Human leukocytes antigens (HLA)?

Answer 10

Human proteins

Question 11

Why do we have HLA polymorphism?

Answer 11

Theory

High genetic variability within these gees may counteract the Pathogens ability to evade immune responses though their mutation

Question 12

Where do MHC polymorphisms take place?

Answer 12

In the upper binding part of the MHC protein

Question 13

Compare the variability to MHC 1 to MHC 2

Answer 13

MHC 1 has more variability

Question 14

How is there variation in the biding groves of MHC 1?

Answer 14

Variation between different MHC alleles = variation in size, charge an location oof pockets = variations in peptides that can anchor within the pockets

Question 15

What do T cell receptors recognise on NK + CD8 cells?

Answer 15

MC protein itself

Antigenic peptide presented by MHC protein

Question 16

How does a T cell receptor bin to MHC 1?

Answer 16

Binds with a diagonal footprint that cuts across both alpha helices

Question 17

Where does CD8 bind to MHC 1?

Answer 17

Binds to the lower part of MHC 1 (to the support domains)

whereas TCR binds to the alpha1+2 domain

Question 18

What is the role of CD8?

Answer 18

acts as as a co-receptor for MHC-1, and is required for the T cell to make an effective response

Question 19

How can pathogens prevent MHC 1 presentation?

Answer 19

Inhibit MHC1 transcription (adenovirus)

Block peptide transport into endoplasmic reticulum (HSV)

Retain MHC-1 in endoplasmic reticulum (adenovirus, HCMV)

Target MHC-1 for disposal from endoplasmic reticulum (HCMV)

Down regulate MHC-1 from cell surface

Question 20

What is the function of killer ig-like receptors (KIR)?

Answer 20

Bind to MHC-1 and inhibit NK cells from releasing lyric granuels (NK cells survive)

Bind to the same face of MHC-1 as the TCR

A

Question 21

What is meant but the term missing self?

Answer 21

When MHC-1 is not detected there is no inhibition of NK cell lysis so lyric granules will be released - NK cell dies

Question 22

Are killer ig-like receptors (KIR) polymorphic?

Answer 22

Yes

And polymorphic individuals KIR genes vary in their presence between individuals

Question 23

What are natural cytotoxicity receptors?

Answer 23

Receptors that provide activating signals to NK cells, but their range of ligands are not well characterised

Question 24

Give examples of neutral cytotoxic receptors

Answer 24

NKp46
- binds to viral haemaglutinin

Nkp44
- binds a ligand that is expressed on tumour cells + unregulated by infection

Nkp30
- ligand is a stress induced protein

Question 25

What is the balance between inhibitory and riveting signals needed for target cell death or survival?

Answer 25

MHC 1 binding - inhibitory - target cell survives

Activating receptor - activating - target cell lysis

More then one signal then another determines cell lysis or survival

Question 26

Why do NK cells kill tumour cells?

Answer 26

Tumour cells can escape the adaptive immune system by down regulation of MHC 1 expression

Making them more susceptible to NK cells

Question 27

How do Nk cell recognise antibody complexes on target cells?

Answer 27

By Antibody-dependent cell-mediated cytotoxicity (ADCC)

1. Nk cells express receptor that recognises FCC portion of antibodies
2. Receptor delivers a strong activating signal when it recognises antibodies bound to a cell surface
3. Results in lysis of target cell

Question 28

Describe the mechanism of lysis

Answer 28

1. NK and T cells carry granules containing proteins

2 The cytotoxic granuels are released at the site of contact with the target cell

Must be directed to avoid damaging innocent bystander cells

Question 29

What proteins are in the granules do cytotoxic T cells?

Answer 29

Perforin - aids in delivering contents of granules into the cytoplasm of target cells

Granzymes - serine proteases, which activates apoptosis once in the cytoplasm of the target cell

Granulysin - has anti microbial actions and can induce apoptosis

Question 30

What is meant by a immunological synapse?

Answer 30

T cell receptor and CD8 cluster at the site of cell-cell contact

This polarises the T cell to release effector molecules at the point of contact

Question 31

How can CD8 cells trigger apoptosis of target cells using Fas/FasL interaction?

Answer 31

Slower process than cytotoxic granules

1. Fas LIGAND on T cells engages Fas on target cells to trigger apoptotic pathway
2. FADD binds to Death domain on Fas
3. Pro-caspase 8 then binds to death effector domain triggering a cascade

Fa/FasL triggered apoptosis is used to dispose of unwanted lymphocytes

Question 32

What can occur as a result of loss of Fas?

Answer 32

Autoimmune lymphoproliferation syndrome (ALPS)

Question 33

compare cytotoxic T cells and NK cells

Answer 33

T cells
- CD8 as a co-receptor for MHC-1
- Each express a unique an highly specific T cell receptor
- presence of appropriate MHC-1 ligand results in activation of Killing response
- absence of HC 1 ligand causes cell to move n after no recognition
- Response equites initial activation of naive T cells, followed by differentiation and proliferation

NK cells
- Do not use a co-receptor
- express multiple receptors including activating and inhibitory receptors
- Absence of appropriate MHC-1 ligand results in activation of killing response
- ready to act on encountering targets in periphery

Question 34

REVISION TASK

Answer 34

MAKE A TABLE COMPARING NK AND CD8 CELLS