Lecture 31 - NK Cells

Question 1

How were NK cells first observed?

Answer 1

Lymphocytes in mice were observed to kill tumour cells

Question 2

Adherent cells in the spleen

Answer 2

Macrophages

Question 3

Surface markers identifying T cells

Answer 3

CD3, TCR

Question 4

NK cell identifying surface markers 
1)
2)
3)
4)
5)

Answer 4

1) CD3/TCR -
2) Surface IG -
3) CD161 (NK1.1) +
4) CD56 +
5) CD16 can be present, but not always

Question 5

NKT cell identifying surface markers
1)
2)
3)

Answer 5

1) CD3/TCR +
2) Surface IG -
3) CD161 (NK1.1)

Question 6

Features of NK cells
1)
2)
3)
4)

Answer 6

1) Innate lymphocytes
2) Lack antigen-specific Ig receptors
3) Express a number of receptors that control activation
4) Thought not to undergo clonal expansion, but this is being challenged

Question 7

Time after viral infection that NK response peaks

Answer 7

~3 days

Question 8

Cytokine that induces NK response

Answer 8

IFNg

Question 9

NK cell functions
1)
2)
3)

Answer 9

1) Lysis of target cells (perforin, granzymes, Fas/FasL)
2) Secrete cytokines (IFNg, TNFa)
3) Secrete chemokines

Question 10

Things that can activate NK cells
1)
2)
3)

Answer 10

1) Cytokines (IL-12, IL-15, IL-18, IFNg)
2) Cellular interactions (antibody-dependent cellular cytotoxicity)
3) Natural cytotoxicity

Question 11

Antibody-dependent cellular cytotoxicity
1) 
2) 
3) 
4)

Answer 11

1) IgG binds to target cell
2) IgG detected by CD16 (FcgRIII) on NK cell
3) CD16 is associated with a CD3-like adaptor that has ITAMS
4) Lysis of cell

Question 12

Natural cytotoxicity
1)
2)
3)

Answer 12

1) An innate ability of NK cells, doesn’t require antibodies
2) Kills virus-infected cells
3) MHCI inhibits NK cell activation. NK cell inspects target cell, if target cell lacks MHCI, killed

Question 13

Cells susceptible to NK lysis
1)
2)

Answer 13

1) Some viruses downregulate MHCI expression to avoid CD8+ detection. NK cells kill these
2) Tumour cells often have defective MHCI

Question 14

Viruses that interfere with MHCI expression
1)
2)
3)

Answer 14

1) Cytomegalovirus
2) Herpes simplex virus
3) HIV

Question 15

3 types of inhibitory receptors in NK cells

Answer 15

1) Ly49
2) Killer-cell immunoglobulin-like receptors (KIR, CD158)
3) CD94/NKG2A

Question 16

Ly49
1)
2)
3)

Answer 16

1) Inhibitory receptor expressed by rodent NK cells
2) Members of C-type lectin superfamily
3) Recognise H-2D, H-2K class I molecules

Question 17

Killer cell immunoglobulin-lie receptors (KIR)
1) 
2) 
3) 
4)

Answer 17

1) Expressed by primate NK cells
2) Family of receptors (CD158a-f)
3) Members of Ig-like superfamily
4) Recognise HLA-B (Bw4) and HLA-C MHCI molecules (and some HLA-A)

Question 18

MHCI molecules recognised by KIR

Answer 18

HLA-B (Bw4), HLA-C, some HLA-A

Question 19

CD94/NKG2A
1)
2)
3)

Answer 19

1) Highly conserved through evolution
2) Members of C-type lectin superfamily
3) Recognises non-classical MHCI (HLA-E in humans)
4) Ubiquitous expression, non-polymorphic (only 2 alleles in human population)

Question 20

What do NK inhibitory receptors signal thorough?

Answer 20

ITIMs (Immunoreceptor tyrosine–based inhibitory motifs)

Question 21

Ly49 ITIM configuration

Answer 21

Ly49 is a dimer, one ITIM per cytosolic part of Ly49 monomer

Question 22

CD158 ITIM configuration

Answer 22

2 ITIMs per cytosolic region of CD158

Question 23

CD158

Answer 23

Killer cell immunoglobulin-like receptor (KIR)

Question 24

Another name for killer cell immunoglobulin-like receptor

Answer 24

CD158

Question 25

How do NK inhibitory receptors signal? 1) 2) 3)

Answer 25

1) Receptor is bound 2) ITIM Is phosphorylated 3) SHIP is activated, which prevents NK cell activation

Question 26

``` Different forms of killer cell immunoglobulin-like receptor 1) 2) 3) 4) ```

Answer 26

1) Have either 2 or 3 extracellular domains 2) Are either S or L form (short cytoplasmic tail or long cytoplasmic tail form) 3) S forms lack ITIMs. L forms have ITIMs. 4) S lack ITIMs, so aren't actually inhibitory receptors

Question 27

What do different domain-types of killer cell immunoglobulin-like receptors do?

Answer 27

Detect different HLA types

Question 28

CD158a

Answer 28

2DL1

Question 29

CD158b

Answer 29

2DL2/3

Question 30

What do killer cell immunoglobulin-like receptors 2DL1 and 2DL2/3 detect?

Answer 30

HLA-C group 1 and 2

Question 31

What does CD158a detect?

Answer 31

HLA-C group 2

Question 32

What does CD158b detect?

Answer 32

HLA-C group 1

Question 33

Which NK cell receptor detects Bw4?

Answer 33

KIR 3DL1

Question 34

What does KIR 3DL1 detect?

Answer 34

Bw4

Question 35

What does KIR 3DL2 detect?

Answer 35

A3/A11

Question 36

Which NK cell receptor detects HLA A3/A11?

Answer 36

KIR 3DL2

Question 37

Number of MHCI epitopes recognised by KIR

Answer 37

4 | These are mutually exclusive. A MHCI can only be one of these types

Question 38

``` MHCI epitopes recognisable by KIR 1) 2) 3) 4) ```

Answer 38

1) Group 1 HLA-C (or C-1) 2) Group 2 HLA-C (or C-2) 3) Bw4 4) A3/A11

Question 39

Do all HLA alleles possess either C1, C2, Bw4 or A3/A11 determinants?

Answer 39

No. | This is thought to minimise competition between CD8+ and NK cells

Question 40

HLA types that often don't possess NK-recognised epitopes

Answer 40

HLA-A and HLA-B

Question 41

HLA alleles that KIR mostly recognises

Answer 41

HLA-C

Question 42

What defines Bw4/Bw6 HLA-B alleles? 1) 2)

Answer 42

1) Specific amino acid sequence between amino acids 77 and 83. 2) This sequence lies within the alpha-helix which makes up part of the binding groove of HLA-B

Question 43

What defines C1 and C2 HLA-C alleles?

Answer 43

Amino acid 80 asparagine or lysine

Question 44

KIR HLA binding site

Answer 44

On the join between the two Ig-like domains of the protein

Question 45

Where on an MHCI molecule do KIR normally bind?

Answer 45

The edges

Question 46

Is there variation in which inhibitory receptors NK cell express?

Answer 46

Yes.

Question 47

``` Why might it be beneficial for NK cells to express different inhibitory molecules? 1) 2) 3) 4) ```

Answer 47

1) Some viruses (EG: HIV with nef) inhibit the expression of some MHCI alleles (HIV inhibits HLA-A, HLA-B, doesn't affect HLA-C) 2) Some NK cells will be inhibited by HLA-C expression, but some NK cells lack inhibitory receptors for HLA-C 3) These NK cells will be able to kill HIV-infected cell 4) Normal cells express HLA-A, HLA-B and HLA-C, so aren't killed by NK cells

Question 48

Allele of NK surface receptor that results in delayed progression to AIDS 1) 2)

Answer 48

1) Bw4 | 2) Nef-mediated downregulation of Bw4 leads to killing of infected cells

Question 49

Effect of allotype on acute myeloid leukaemia patients

Answer 49

If there is a KIR-ligand mismatch between patient and bone-marrow donor, then NK cells are produced that kill tumour cells

Question 50

KIR that recognises HLA-Bw4

Answer 50

CD158e