Lecture 32 - NK Cells II

Question 1

Outcome of alloreactive donor-derived NK cells (bone marrow transplant)
1)
2)
3)

Answer 1

1) Better engraftment
2) Better leukaemia control
3) No graft versus host disease

Question 2

CD158 receptors that inhibit NK cell killing

Answer 2

Only CD158 with long (L) tails have ITIMs, which are what inhibit NK cell killing

Question 3

What controls NK cell activity?

Answer 3

A combination of stimulatory and inhibitory signals

Question 4

NK cell activating receptors
1)
2)
3)

Answer 4

1) CD158(s)
2) CD16
3) NKG2D

Question 5

NK cell inhibitory receptors
1)
2)
3)

Answer 5

1) CD158(l)
2) Ly49
3) MHCI

Question 6

Why do patients receiving a bone-marrow transplant with alloreactive NK cells have no graft-versus-host disease?
1)
2)

Answer 6

1) NK cell mismatch leads to killing of DCs in periphery

2) Non-donor bone marrow-derived DCs can no longer activate T cells against self MHCII

Question 7

Cause of graft-versus-host disease
1)
2)
3)
4)
5)

Answer 7

1) Dendritic cells are bone-marrow derived, therefore are derived from donor bone marrow
2) DCs are responsible for negative selection of T cells
3) Cortical epithelial cells aren’t bone-marrow derived
4) There will be no negative selection of T cells that react to MHCII from host
5) DCs from periphery (that display host MHCII) activate T cells, which then go and kill self cells inperiphery

Question 8

NK cell receptors that activate NK cells
1)
2)
3)
4)

Answer 8

1) Adhesion molecules CD2, 2B4
2) Natural cytotoxicity receptors NKp30, NKp44, NKp46
3) Activating forms of CD158, Ly49
4) NKG2D

Question 9

CD2 and 2B4 ligands

Answer 9

On haematopoietic cells.

This might be why NK mismatch is so effective against leukaemias

Question 10

Activating forms of Ly49, CD158 ligands

Answer 10

Unknown.

Might be MHCI

Question 11

which cells express NKG2D?

Answer 11

All NK cells, some T cells

Question 12

NKG2D effects
1)
2)
3)

Answer 12

1) Potent activator of NK cells
2) T cell costimulation (gamma/delta and CD8+)
3) Enhanced TNFa and NO activity in macrophages

Question 13

Human NKG2D ligands
1)
2)

Answer 13

1) MIC A/B

2) ULBP

Question 14

Murine NKG2D ligands
1)
2)

Answer 14

1) Retinoid acid early inducible transcripts (RAE-1)

2) H60

Question 15

Common features of NKG2D ligands
1)
2)
3)

Answer 15

1) All MHCI-like (two alpha helices over a beta sheet)
2) Don’t bind peptides
3) Don’t bind beta2-microglobulin

Question 16

Why can’t NKG2D ligands bind peptide?

Answer 16

The binding groove is too narrow

Question 17

NKG2D ligand expression
1)
2)
3)

Answer 17

1) Inducible (not constitutive)
2) Low or absent expression in most adult tissues
3) Induced by cellular stress

Question 18

What can induce NKG2D expression?
1)
2)
3)
4)
5)
6)

Answer 18

1) Cellular stress, in response to metabolic perturbations
2) Heat shock
3) Viral infection (EG: CMV)
4) Mycobacterial infection
5) Pathogenic E coli
6) Tumour cells

Question 19

Which intracellular factors initiate NKG2D-ligand expression?

Answer 19

Protein kinases ATM and ATR

Question 20

What causes protein kinases ATM and ATR to induce NKG2D-ligand expression?
1)
2)
3)

Answer 20

1) DNA damage
2) dsDNA breaks
3) Stalled replication forks

Question 21

What can override NK cell inhibitory signals?

Answer 21

NKG2D signals

Allows NK cells to kill target cell, even if target cell expresses MHCI

Question 22

CMV infection natural history
1)
2)

Answer 22

1) Replicates in the liver and spleen between days 1 and 8-10
2) Establishes a chronic infection in the salivary glands

Question 23

Host genes that can regulate CMV infection
1)
2)

Answer 23

1) Ly49H in mice

2) CD94- NKG2C+ in humans (maybe)

Question 24

Mouse strain that has high CMV titres in spleen and liver, but ultimately clears virus

Answer 24

BALB/c

Question 25

Mouse strain that has low CMV titres in spleen and liver, but has a chronic

Answer 25

C57B6

Question 26

Ly49H ligand

Answer 26

Recognises m157, and MHCI-like molecule expressed by murine CMV

Question 27

What does Ly49H signal through?

Answer 27

DAP12, a CD3-like receptor adaptor molecule that contains ITAMs

Question 28

Mice that Ly49H is present in

Answer 28

C57B6

Question 29

Evidence for NK cell oligoclonal expansion

Answer 29

In mice with mCMV, Ly49H+ NK cells are preferentially expanded

Question 30

Evidence for NK cell memory
1)
2)

Answer 30

1) After an infection with mCMV, C57B6 mice have greater levels of Ly49H+ NK cells than before infection
2) Greater proportion of ‘memory’ NK cells secrete IFNg than non-memory

Question 31

Do NK cells undergo contraction after expansion?

Answer 31

Yes.

Similar to a CD8+ response

Question 32

Why does CMV express m157 if it is recognised by NK cells?

Answer 32

Allows virus to establish a chronic infection in salivary glands

Question 33

Effects of mCMV in mice without Ly49H
1)
2)
3)
4)

Answer 33

1) Elevated viral load
2) More antigen
3) Robust T cell response
4) More effective viral clearance

Question 34

Effects of mCMV in mice with Ly49H
1)
2)
3)
4)
5)

Answer 34

1) Better acute control of virus
2) Less pathology
3) Increased killing of infected DCs
4) Impaired T cell responses (from killed DCs)
5) Viral persistence

Question 35

Interleukin that allows NK cell expansion

Answer 35

IL-12

Question 36

Ways to activate NK cells
1)
2)
3)
4)

Answer 36

1) Missing self
2) Induced self
3) Direct recognition of viral glycoproteins
4) Cytokine-dependent activation

Question 37

Cytokines that activate NK cells
1)
2)
3)
4)

Answer 37

1) IFNa
2) IL-12
3) IL-15
4) IL-18