Natural born killers

Question 1

What is innate immunity?

Answer 1

• Innate is relatively non-specific/broadly specific and immediate response

Question 2

What is adaptive immunity?

Answer 2

• Adaptive is highly specific and theirs a delayed response

Question 3

Where do both natural killer cells and T cells both originate from and so what are both?

Answer 3

Natural killer cells and T cells both originate from common lymphoid progenitor cells, so both are lymphocytes

Question 4

What are cytotoxic cells used to destroy?

Answer 4

Cytotoxic cells are used to destroy our own cells that are infected with bacteria/viruses/parasites or tumour cells

Question 5

Where are MHC class proteins found and what do they form?

Answer 5

MHC class proteins are found at the cell surface and form a structure that holds antigenic peptides for surveillance by T cells

Question 6

What cells are MHC class I recognised by?

Answer 6

• MHC class I is recognised by CD8.+ cytotoxic T cells

Question 7

What are all normal and viral proteins presented by?

Answer 7

• All normal proteins as well as viral proteins are presented by MHC class I

Question 8

How do adenoviruses stop their peptides from getting presented on MHC class I?

Answer 8

§ Inhibit MHC-I transcription

Question 9

How does HPV stop their peptides from getting presented on MHC class I?

Answer 9

§ Blocks TAP activity
□ This is the transporter which gets peptides from cytoplasm into ER
§ MHC-I remains empty

Question 10

How does HCMV stop their peptides from getting presented on MHC class I?

Answer 10

§ Retains MHC-I in ER or targets MHC-I for disposal from ER

Question 11

How does HIV stop their peptides from getting presented on MHC class I?

Answer 11

§ Downregulates MHC-I from cell surface

Question 12

What structural domains does MHC class I have?

Answer 12

MHC class I has the structural domains alpha-3 and beta2 macroglobulin

Question 13

What are the structural domains in MHC class I for?

Answer 13

○ Largely there to provide support to the peptide binding groove on top

Question 14

What is MHC class I found on?

Answer 14

• MHC class I is found on every nucleated cell

Question 15

What HLA do humans have?

Answer 15

• Humans have HLA-A, B or C

Question 16

What are MHC class I proteins central to?

Answer 16

• MHC class I proteins are central to anti-viral immune responses

Question 17

Where are polymorphisms found in the MHC protein and what does this decide?

Answer 17

• Polymorphisms are found in the upper peptide part of the MHC protein
     § This decides what peptides the MHC class can bind to

Question 18

What do amino acids in the MHC peptide groove create?

Answer 18

• Amino acids in the MHC peptide groove create pockets where the bound peptide can anchor

Question 19

What do MHC class I and II play a central role in?

Answer 19

• MHC class I and II play a central role in the ability of the immune system to distinguish self from non-self

Question 20

What are the 2 things TCR recognise?

Answer 20

• TCRs recognise 2 things:
○ The MHC protein itself
○ The antigenic peptide presented by the MHC protein

Question 21

How does TCR bind with MHC protein and what does this help the TCR with?

Answer 21

• TCR binds with a diagonal footprint that cuts across both alpha helices with the peptide in between
○ This helps TCR to bind to both the MHC and the peptide

Question 22

What is the interaction between the TCR and MHC-I and therefore what is used to make an effective response.

Answer 22

• For cytotoxic T cells, the interaction between the TCR and MHC-I isn’t very strong
○ Therefore use CD8 as a co-receptor to make an effective response

Question 23

What domain does TCR bind to and where is it located?

Answer 23

• TCR binds to the alpha1alpha2 domains which is at the top of the MHC

Question 24

What does CD8 bind to and what is the reason for?

Answer 24

• CD8 bind to the support domains at the bottom of the MHC

§ This is the reason for the lack of polymorphism at the bottom if the MHC, hence highly conserved

Question 25

What are natural killer cells?

Answer 25

• Large granular lymphocytes that are not T/B cells

Question 26

What do natural killer cells generally express?

Answer 26

• Generally express the cell surface marker CD56

Question 27

What are the 2 major functions of natural killer cells?

Answer 27

1. Cytokine secretion | 2. Cytotoxic functions

Question 28

What function was associated with reduced cancer risk?

Answer 28

• Medium and high cytolytic function was associated with reduced cancer risk whereas low cytolytic function was associated with increased cancer risk

Question 29

What are killer Ig-like receptors(KIR)?

Answer 29

Killer Ig-like receptors(KIR) are innate immune receptors that regulate the activity of natural killer cells

Question 30

What are leukocyte Ig-like receptors?

Answer 30

• Leukocyte Ig-like receptors(LILR) are innate immune receptors that regulate the functions of NK cells

Question 31

What happens when a KIR recognises a MHC-I?

Answer 31

inhibits NK cells from releasing lytic granules

Question 32

What do some viruses do to evade cytotoxic T cells?

Answer 32

• Some viruses down regulate MHC-I as a means to evade cytotoxic T cells

Question 33

What is the loss of MHC-I a common feature of?

Answer 33

• Loss of MHC-I is also common feature of tumour cells

Question 34

What happens to KIR if the target cell doesn't express MHC-I and what does this cause?

Answer 34

• If a target cell doesn't express MHC-I, then there's no KIR inhibition § This causes lytic granules to be released to lyse the target

Question 35

What does inhibitory KIR bind to the same face of as the T cell receptor?

Answer 35

• Inhibitory KIR bind to the same face of MHC-I as the T cell receptor

Question 36

Why are KIR polymorphic?

Answer 36

• KIR are also polymorphic as KIR genes vary in their presence between individuals

Question 37

What do different MHC-I/KIR combinations show?

Answer 37

• Different MHC-I/KIR combinations show disease associations

Question 38

What do natural cytotoxicity receptors(NCR) provide?

Answer 38

• These provide activating signals to NK cells but are not well characterised

Question 39

What does NCR 1 bind?

Answer 39

• NCR 1 binds viral haemagglutinin

Question 40

What does NCR 2 bind?

Answer 40

• NCR 2 binds a ligand that is expressed in tumour cells and upregulated by viral infection

Question 41

What does NCR 3 bind?

Answer 41

• NCR 3 binds a ligand that is stress induced

Question 42

How can tumour cells escape the adaptive immune system and what does it make tumour cells more susceptible to?

Answer 42

``` • Tumour cells can escape the adaptive immune system by downregulating the expression of MHC class I § Become more susceptible to NK cells ```

Question 43

What do NK cells and T cells carry?

Answer 43

• NK cells and T cells carry granules filled with cytotoxic proteins

Question 44

At what site are cytotoxic granules containing released and what are they?

Answer 44

Release cytotoxic granules containing proteins at site of contact with target cells 1. Perforin 2. Granzymes 3. Granulysin

Question 45

What do perforins help deliver?

Answer 45

§ Helps deliver contents of granules into cytoplasm of target cells

Question 46

What do granzymes activate?

Answer 46

§ Activate apoptosis once in cytoplasm of target cell

Question 47

What does granulysin have and what can it induce?

Answer 47

§ Has antimicrobial properties and can induce apoptosis

Question 48

Why must cytotoxic granules be directed?

Answer 48

• Must be directed in order to avoid damaging innocent bystander cells

Question 49

What do CD8 cells trigger apoptosis of target cell through?

Answer 49

• CD8 cells can also trigger apoptosis of target through Fas/FasL interaction

Question 50

Apoptotic pathway Fas/FasL interaction

Answer 50

○ FasL on T cell interacts with Fas protein on target cells ○ Binding trimerizes death domain on Fas protein ○ Interacts with Fas associated death domain(FADD) ○ FADD has a death effector domain(DED) which converts pro-caspase 8 to caspase 8 ○ Triggers the extrinsic apoptotic pathway

Question 51

What is Fas/FasL triggered apoptosis used to dispose?

Answer 51

• Fas/FasL triggered apoptosis is used to dispose of unwanted lymphocytes

Question 52

What can loss of Fas result in?

Answer 52

• Loss of Fas can result in autoimmune lymphoproliferative syndrome(ALPS)