Lecture 32 - NK Cells II Flashcards
Outcome of alloreactive donor-derived NK cells (bone marrow transplant)
1)
2)
3)
1) Better engraftment
2) Better leukaemia control
3) No graft versus host disease
CD158 receptors that inhibit NK cell killing
Only CD158 with long (L) tails have ITIMs, which are what inhibit NK cell killing
What controls NK cell activity?
A combination of stimulatory and inhibitory signals
NK cell activating receptors
1)
2)
3)
1) CD158(s)
2) CD16
3) NKG2D
NK cell inhibitory receptors
1)
2)
3)
1) CD158(l)
2) Ly49
3) MHCI
Why do patients receiving a bone-marrow transplant with alloreactive NK cells have no graft-versus-host disease?
1)
2)
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
Cause of graft-versus-host disease 1) 2) 3) 4) 5)
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
NK cell receptors that activate NK cells 1) 2) 3) 4)
1) Adhesion molecules CD2, 2B4
2) Natural cytotoxicity receptors NKp30, NKp44, NKp46
3) Activating forms of CD158, Ly49
4) NKG2D
CD2 and 2B4 ligands
On haematopoietic cells.
This might be why NK mismatch is so effective against leukaemias
Activating forms of Ly49, CD158 ligands
Unknown.
Might be MHCI
which cells express NKG2D?
All NK cells, some T cells
NKG2D effects
1)
2)
3)
1) Potent activator of NK cells
2) T cell costimulation (gamma/delta and CD8+)
3) Enhanced TNFa and NO activity in macrophages
Human NKG2D ligands
1)
2)
1) MIC A/B
2) ULBP
Murine NKG2D ligands
1)
2)
1) Retinoid acid early inducible transcripts (RAE-1)
2) H60
Common features of NKG2D ligands
1)
2)
3)
1) All MHCI-like (two alpha helices over a beta sheet)
2) Don’t bind peptides
3) Don’t bind beta2-microglobulin
Why can’t NKG2D ligands bind peptide?
The binding groove is too narrow
NKG2D ligand expression
1)
2)
3)
1) Inducible (not constitutive)
2) Low or absent expression in most adult tissues
3) Induced by cellular stress
What can induce NKG2D expression? 1) 2) 3) 4) 5) 6)
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
Which intracellular factors initiate NKG2D-ligand expression?
Protein kinases ATM and ATR
What causes protein kinases ATM and ATR to induce NKG2D-ligand expression?
1)
2)
3)
1) DNA damage
2) dsDNA breaks
3) Stalled replication forks
What can override NK cell inhibitory signals?
NKG2D signals
Allows NK cells to kill target cell, even if target cell expresses MHCI
CMV infection natural history
1)
2)
1) Replicates in the liver and spleen between days 1 and 8-10
2) Establishes a chronic infection in the salivary glands
Host genes that can regulate CMV infection
1)
2)
1) Ly49H in mice
2) CD94- NKG2C+ in humans (maybe)
Mouse strain that has high CMV titres in spleen and liver, but ultimately clears virus
BALB/c
Mouse strain that has low CMV titres in spleen and liver, but has a chronic
C57B6
Ly49H ligand
Recognises m157, and MHCI-like molecule expressed by murine CMV
What does Ly49H signal through?
DAP12, a CD3-like receptor adaptor molecule that contains ITAMs
Mice that Ly49H is present in
C57B6
Evidence for NK cell oligoclonal expansion
In mice with mCMV, Ly49H+ NK cells are preferentially expanded
Evidence for NK cell memory
1)
2)
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
Do NK cells undergo contraction after expansion?
Yes.
Similar to a CD8+ response
Why does CMV express m157 if it is recognised by NK cells?
Allows virus to establish a chronic infection in salivary glands
Effects of mCMV in mice without Ly49H 1) 2) 3) 4)
1) Elevated viral load
2) More antigen
3) Robust T cell response
4) More effective viral clearance
Effects of mCMV in mice with Ly49H 1) 2) 3) 4) 5)
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
Interleukin that allows NK cell expansion
IL-12
Ways to activate NK cells 1) 2) 3) 4)
1) Missing self
2) Induced self
3) Direct recognition of viral glycoproteins
4) Cytokine-dependent activation
Cytokines that activate NK cells 1) 2) 3) 4)
1) IFNa
2) IL-12
3) IL-15
4) IL-18
