Nk cells II Flashcards
What is licensing?
Tunes NK cells to their microenvironment, makes sure that if they see lots of inhibitory signal, that they can become more responsive to decreases.
If they see lots of activator signals at stable state, then you need them to be less responsive and require higher levels of activatory signals to respond.
If in NK development, NK cells are exposed to stronger inhibitory R:L interactions, will NKs be hyper or hypo responsive?
They will be hyper reponsive.
If NK cells are develped in MHC 1 deficient mice, will they be hyper or hyporesponsive?
They will reeive weaker inhibtiory signals in licencing and will be hyporesponsive.
If NK cells licensed (but have no inhitiroy receptors for MHC 1) will they be hyper hypo responsive?
They receive almost no inhbitory signals, so hyporesponsive.
If NK cells that express activatory receptors NKG2D and murine Ly49H in trangenic mice expressing their lgiands, hypo or hyper responsive?
They receive more activatory signals during licensing, so will be hyporesponsive (think that in environemtn there is higher levels of activator signals it has to ‘ignore’).
If you lack activing receptors, will NK cells be hyper or hypo responsive during licensing?
They will not receive any activatory signals, assume environment has no activator signals, to compensate need to be hyperreactive.
What models for licencisnig are there?
arming, disarming, rheostat.
Disarming theory f
Arming theory for licensing?
Arming, NK cells intrinsically hyporesponsive, and inhibitory signalling will ‘arm’ and increase their capacity for activation.
Disarming theory for licensing?
NK cells are intrinsically hyperresponsive, and inhibitory signalling will dampen their responsiveness.
Rheostat theory for licensing?
Intrgration of signals for multiple of NK receptors to determine their competency.
What things may affect/explain licensing?
DIfference between ITAM and ITIM signalling.
Or licensing induces clustering of inhibitory and activating receptors.
Some HLA-A types are associated with poorer HIV prognosis, why might NK licensing explain this?
HLA-A increases the number of signal peptides that can be expressed by HLA-E and recognised by NKG2A (inhibitory receptor).
However, moving balance away from inhibitory KIRs to inhibitory NKG2A can reduce the potency of NK cells.
Why might expansion and adaptive NK cell therapy of allogeneic as well as autologous NK cells work?
Because autologous NK cells may be incompletly inhibited- greater activation and anti tumour killing.
What problems might you have to overcome?
How to traffic and home NK cells, and overcome tumour microenvironment and immunosuppression.
Could you use immortal NK cell lines?
Potentially yes, rarely turn oncogneic and if they did not so many clinical complications.
Problem with using IL-2 to expand them?
Can also end up expanding Tregs.
How to make NK cells more potent for tumour therapy?
Reudce their inhibitory receptors and increase activatory receptors.
Can do this with GE, or with immunomodulatory drugs.
Use in conjunction with checkpoint inhibitors.
How could therpeutic antibodies work in conjucntion with NK cells?
Therapeutic antibodies against TAs could increase ADCC.
Could block NK inhibitory receptors.
How might binding of soluble MICA/B help NK cell therapy?
Mops up soluble MICA/B which chronically has caused NKG2D downregulation. And will bind to MICA/B expressed on suppressive myeloid cells.
CAR NK Cells?
Create activatory receptors coupled with multiple activatory domains e.g. of different activator molecules and adaptor molecules.
Overcomes inhibitoin.
How might bi/tris specific Ab and Il-2 mutants help NK cell activation?
bi specific Ab can agonise NK activaory receptors and bring into contact with TAs.
IL-2 mutants that only bind high affinity IL2aBy receptor.
What are CD25 and CD122?
They are the IL-2a and IL15 B receptor.
Tissue specific NK cells are also found where? 3 examples?
Uterus, spleen and liver.
Phenotype of unique NK T cells in the uterus?
CD56high CD16- and CD94/NKG2A+
What are uterine NK cell recptor profiles like?
Many activating recepotrs, and many KIR recepotrs, especially those that recognise HLA-C.
What kind of cytokines might NK cells produce? And what might their function be?
Produce IFN-y and other tissue remodelling factors like EGF and Ang 1+2.
Important for extravillous trophoblast invasion of the spiral arteries.
What are changes in uterine NK cells associated with?
Associated with recurrent miscarriages, pre-eclampsia and endometriosis..
What do CD94/NKG2A and LILRB1 receptors on uterine NK cells bind to and do?
NKG2A will bind to HLA-E, thought to prevent NK killing.
LILRB1 binds to HLA-G dimers, might be important for tolerogenic effects.
How might changes in NK cells affect endometriosis?
Changes may affect the abiliity of cytotoxic NK cells to remove ectopic endometrium.
What two KIRs are associated with improved with slower progression of HIV in patients with HLA-B w4lso80 allotype?
Both KIR 3DRS1 and the inhibitory receptor KIR 3DL1 bind this HLA allele.
How higher expression of the stimulatory receptor helps mechansitcally not so clear (education or elimination)
The high binding of inhibitory KIR 3DL1 is thought to help increase hyperresponsiveness post licensing.
Are activatory KIRs associated generally with good outcomes in cancer and infection?
Associated with bad outcomes in cancer, but good outcomes in infection, though mechanisms not understood!
How does CMV avoid NK cell activation?
Produces lots of decoy MHC 1 like receptors like UL18, which also associates with B2m.
Can produce UL40, which is cleaved in membrane and loaded onto HLA-E to replace the leading sequence that is no longer loaded due to TAP inhibition.
How does HIV evade NK cells?
Stimulation of both activatory recepotrs NKG2D and NTB-A is required for activation.
Vpu from HIV will remove the NTB-A ligand (NTB-B) from surface.
What are the indications that NK cells can have ‘memory’
Some NK cells undergo epigentic modifications following infection.
NK cells can undergo T cell like expansion and contraction.
Persist in higher frequencies and self renew post infection.
Phenotypically they resemble T cells markers.
element of antigen specificity.
Memory group of NK cells in mice?
The Ly49H group which recognises CMV antigens. ONly present in mice infected with CMV.
What memroy cell gropu of NK cells do humans show?
Who are they seen in?
NKG2C+ activatory HLA-E receptor. Recognise the CMV loaded UL40 leading sequence.
Only seen in people seropositive for CMV.
What changes in memory cells are seen upon PLZ4 silencing?
Generally downregulation of adaptor molecules important for especially activatory signalling. e.g. FcERy signalling downregulated.
Attenuates SLAM and other activatory receptors.
May push towards CD16 ADCC signalling.
Reorganisation of receptor repertoire.
What other epigenetic changes in NK memory cells?
hypomethylation of IFN-y and TNFa, faster and greater cytokine expression upon stimulation.
The epigenetic changes are heterogeneous amongst memory NK cells.
May also find CD56 negative cells, when NK cells lose their expression. Does this have functional effects?Who are they found most in?
Decreases their functionality
Those with chronic infections, ageing people.
What other strange population of NK cells seen?
NKp46 high NK cell population, also in chronic infection. May be good for infections, but predictors of failure to IFN-y therapy.
