Flashcards in NK Cell Functions Deck (36):
How are NK cells activated during viral infection?
By IFNa and IFNb released during viral infection.
When is the NK cell response activated?
2 days after infection.
Describe what happens when an NK cell encounters a normal, healthy cell.
There is more MHC class I expressed than activatory ligands on the normal cell, meaning that the NK cell inhibitory signal dominates and there is no induction of apoptosis.
Explain the missing-self hypothesis in terms of NK cell activation.
Target cell does not express MHC class I, meaning there is no inhibitory signal, and the activating signals become dominant - activating the NK cell to trigger apoptosis of the target cell.
How can there still be NK cell activation if MHC class I expression is maintained by the target cell?
There can be upregulation of the activatory ligands, allowing the activating signals to become dominant, and the NK cell can trigger apoptosis of the target cell.
How does the CD16 Fc receptor activate NK cells?
Recognises antibodies bound to tumour antigens, or on the surface of infected cells -> promotes ADCC. Balance is shifted towards an activatory response as tumour cells overexpress the TSA.
Give the cytokines produced by NK cells.
IL-10 and IFNy - act upon macrophages and T cells.
How can NK cells dampen the immune response once an infection has been cleared?
Can kill immature DCs, hyperactivated macrophages, and activated CD4+ T cells.
How do NK cells promote DC maturation?
Through the release of IFNy and TNFa.
What is the outcome of DC maturation?
Enhanced antigen presentation to T cells.
Give cytokines released by macrophages and DCs to stimulate NK proliferation.
Type I interferons, IL-15, IL-12 and IL-18.
Give human ligands for NKG2D.
MICA, MICB and ULPB family members.
Give murine ligands for NKG2D.
H60, MULT1 and Rae-1 family members.
How is MCMV infection detected in mice?
Ly49h receptor on NK cells recognises an MCMV homolog of MHC class I, expressed by infected cells.
How is immune evasion achieved in HCMV?
UL16 is a viral protein that blocks externalisation of ULPB in HCMV-infected cells, preventing activation of NK cells.
What are KIRs?
Mainly inhibitory receptors that recognise MHC Class I and HLA-C.
What is Ly49h equivalent to in humans?
Discuss the evolution of KIRs and Ly49h.
Thought to have evolved separately despite having the same function, and there is no homology between them.
What do activatory KIRs recognise?
HLA-Cw4 - overexpressed in tumour cells.
What is the NKG2A/CD94 heterodimer?
An inhibitory receptor expressed by NK cells that recognises HLA-E.
What is HLA-E?
HLA-E = Human Leukocyte Antigen E
- type of MHC molecule, often upregulated on tumour cells.
How do NK cells kill tumour cells that express the TRAIL receptor?
Produces TRAIL which binds the receptor on the tumour cell and triggers the extrinsic pathway of apoptosis within the tumour cell.
If a tumour cell has not downregulated MHC class I, what does its recognition by NK cells depend on?
The stress ligands expressed by the tumour cell.
Where are the genes for the activatory receptors found in the human genome?
Chromosome 12 (NKC gene cluster)
Where are most of the inhibitory receptor genes encoded in the human genome?
Give the signalling domain in inhibitory receptors. What does this interact with?
ITIMs - interact with SHIP1 phosphatase to inhibit intracellular signalling.
Give the signalling domain in activatory receptors.
Give the proteins that interact with activatory KIRs and NKG2D.
activatory KIRs - interact with DAP12
NKG2D - interacts with DAP10
What do DAP proteins interact with following activation of activatory receptors?
Zap70 tyr kinases
What is NKG2D?
An activatory receptor expressed by all NK cells.
Give the signalling proteins activated following NKG2D activation.
DAP10, DAP12 and PI3K.
Describe the structure of NKG2D.
S=S linked homodimer.
What are MICA, MICB and RAE-1 structurally similar to?
What is NKG2D ligand expression induced by?
DNA damage, cellular stress and metabolic stress.
Give evidence for the NK cell memory in response to MCMV infection.
- WT NK cells are transferred to immunodeficient (DAP12 -/-) mice, and these mice are infected with MCMV.
- Indicated an expansion of Ly49h+ NK cells (donor) at day 7 post-infection.
- after 50 days, only a few of these cells remained - are these ones memory-like?
- injection of memory-like NK cells into neonatal mice gives increased survival when challenged with MCMV.