NK cells Flashcards
What are NK cells?
Natural killer cells are a subset of Innate Lymphoid Cells but are not T or B cells! Precursors give rise to pre-NK cells to generate NK cells and also can generate innate lymphoid cells 1-3. Transcription factors (e.g. T-bet, RORa) determine phenotypic differences between ILC subsets
Classic NK cells are large granular lymphocytes that dint express TCR or BCR but do express cell surface marker CD56 (useful for identification
Their function is cytotoxic and cytokine secretion. They are there to kill target cells by punching holes, triggering serine protease sand inducing apoptosis -> like CD8+ cytotoxic T cells
What are the different subsets of NK cells:
- Low CD56 expression
- these are the cells specialised for killing and are the majority of circulating NK cells - High CD56 expression
- these have a greater cytokine production rate
- Are only around 10% of NK cells and are predominantly found in secondary lymphoid organs.
What cytokines are produced by NK cells?
- Interferon gamma (IFN-g): has effect on a range of cells
- activation, growth and differentiation of T, B, NK cells and macrophages
- promotes Th1 differentiation
- enhances MHC expression on APC - Tumour Necrosis factor alpha (TNF-a)
- Inflammatory mediator which regulates growth and differentiation of a wide variety of cells
- Selectively cytotoxic for many transformed cells
What types of cytotoxic granules can be released by NK cells
Perforin -> aids in delivering contents of granules into the cytoplasm of target cell
Granzymes -> serine proteases which activate apoptosis once in the target cell cytoplasm
Granulysin -> has antimicrobial actions and can induce apoptosis
How do numbers of NK cells and Infection correlate?
Low NK cell activity correlates with severe disseminating herpesvirus infections
How do NK cells know which cell to kill?
Decision to kill:
• Fc receptor recognition of antibody/antigen complexes
• Balance of activating/inhibitory receptors such as Detection of “missing self” or Detection of “induced self”
• Signals for Kill include
– FC receptors
– Activating and inhibitory receptors on NK cell surface
Explain how NK cells can indue ADCC.
ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC):
- Ab binds antigens on surface of target cells
- Fc receptors on NK cells recognise the bound antigen
- CD16 is also produced -> it comes into contact with the Ab bound antigen and produces a very strong “kill” signal
- Cross linking of Fc receptors signals NK cells to kill the target cell which dies by apoptosis
This mechanism can be manipulated to treat tumour cells (tumour specific Ab)
What are the types of receptors on a NK cell?
NK cells are controlled by a balance of signals from activating and inhibitory receptors.
Inhibitory receptors -> signal through ITIMs (immunoreceptor tyrosine-based inhibitory motif) and are contained in long cytoplasmic tail, inside the NK cell
Activating receptors -> signal through ITAMs (immunoreceptor tyrosine-based activation motif) contained in a short cytoplasmic tail, requires adaptor protein for ITAMS. The signals come from the adaptor proteins for the cell
There are also 2 main types of receptor families:
- Ig-like Receptors such as KIR and LIR encoded on chromosome 19
- C type lectin receptor (NKG receptors)
What are KIR receptors?
Killer Ig-like receptors (KIR) are innate immune receptors that regulate the activity of Natural Killer cells. They recognise MHC-1, bind to the same place as TCR and they can recognise MHC-1 subsets as they are highly polymorphic (not as much as MHC)
They cover an end of the peptide binding groove.
The function of KIRs are to inhibit NK cells from releasing lytic granules. Some viruses down-regulate MHC-I to evade cytotoxic T cells, and tumour cells can cause loss of MHC-I. If a target cell does not express MHC-I then there is no KIR inhibition, lytic granules will be released to lyse the target. This is known as “missing self”
This is important to note in HSCT transplants as you have to match MHC receptor for BM receptor and you want a very close match due to NK cells not destroying the cell
For Leukaemia -> you want a slight mismatch for mild graft-vs- leukaemia disease the donor almost needs to attack -> however this needs to be balanced
What is the “license to kill”?
Different KIR genes will recognise different subsets but you might not have all the genes. We could all potentially have the same KIR genes, we might not have the same MHC to match.
To avoid non-specific NK killing we have NK cell licencing which scientists think occurs during NK cell development. If the target cell doesn’t have the specific MHC molecule for binding then the NK cell is not “licensed to kill”, even though there were in the circulation. However, if there is a signal and match, then there would be a license to kill.
What are LIRs?
Leukocyte Ig-like receptors (LILR) are innate immune receptors that regulate the functions of NK cells and antigen presenting cells
LILR-B have inhibitory motifs (ITIMS) whereas LILR-A have ITAM activator motifs (short tail) and associate with adaptor proteins
LILRB1 (ILT2/LIR1) is expressed by NK cells. It doesn’t bind at the peptide binding groove (unlike KIR), it binds in the conserved part of the MHC so has very little specificity, it just sees MHC-1 and makes it a very powerful immune inhibitor
Describe the C-lectin like receptors (NKG)
CD94 NKG receptors are both activating (CD94 NKG2E/C) and inhibitory (CD94 NKG2A) heterodimeric receptors.
They recognise non-classical (MHC-1) HLA-E on target cells. HLA-E is the leader sequence of classical HLA-A,-B and -C. When MHC leaves the ER, the HLA-E is cleaved off and binds to the cell surface like the classical HLA-E. The inhibitory CD94 NKG2A recognised HLA-E and delivers a inhibitory signal.
