What are the two types of cytotoxic lymphocytes?
Nk cells
Tc cells
When MHC lass 1 levels are normal in a cell what signal is given to NK cells?
Inhibitory signal
If there is no MHC class 1 on a cell but there are some activating signals what is the response of the NK cell?
Will kill the cell. Evolved because a number of virus’ actively induce down regulation of expression of MHC class I, or they inhibit components of antigen presentation in order to avoid killing by cytotoxic T cells.
What s the missing self hypothesis?
That NK cells kill cells that don’t express MHC class 1 (if they also have activating signals).
What receptors and complexes provide the molecular basis for the missing self hypothesis?
KIRs, Ly49 receptors and NKG2A/CD94 complex
What are KIR receptors?
Killer Ig-like receptor.
Recognise MHC-1 in a non-peptide specific way.
Signalling is through ITIMs
What is the NKG2A receptor?
Inhibitory receptor expressed as heterodimer with CD94.
Recognise HLA-E.
Signal through ITIMs
What is the general process by which both NK cells and cytotoxic cells kill?
Inducing apoptosis
Can lymphoid cells only kill once?
No they can kill multiple times
What is the effect of perpherin toxin?
In presence of Ca2+ they change conformation to expose hydrophobic region and insert in plasma membrane and form pores by progressive insertion of monomers.
Why do perpherin pores lead to apoptosis?
Pores form entry for other granules.
In particular for granzymes (serine proteases)
In oxygen independent killing by myeloid cells what is the toxin in the granules that form pores?
Defensins.
TNF then enters pores and induces apoptosis.
In oxygen dependant killing my myeloid cells what catalyses the generation of Nitric oxide?
Nitric oxide synthase
This is upregulated in macrophages and neutrophils by INF-gamma
What is the effect of Nitric oxide at high concentrations?
Inhibit mitochondrial respiration.
In an oxygen dependant killing mechanism by myeloid cells how does NADPH oxidase activation act as a mechanism of killing?
Reduces oxygen to super oxide which is then converted to peroxide in the phagocysidic vacuole.
Secretory granules fuse and add myeloperoxidase which converts hydrogen peroxide to more reactive form. e.g. hypochlorous acid
What is the formula for conversion of hydrogen peroxide and chlorine to hypocholorous acid catalysed by myeloperoxidase?
H2O2 + cl- + H+ –> HOCl +H2O
Why is hypochlorous acid formed?
hypochlorous acid (bleach) is a very potent oxidising agent that will break down and kill bacteria
Can myeloids kill multiple times?
No, they normally kill themselves in the process of killing another cell which explain there short half life
What are extracellular traps?
Nuclear DNA and toxic proteins from secretory granules which is released from neutrophils and this traps and immoilises bacteria.
Activated by PAMPs
What does NET stand for?
Neutrophil extracellular traps
Roughly how does killing by extracellular traps take?
Hours
What is difference between eosinophils and neutrophil extracellular traps?
Eosinophils release MITOCHONDRIAL DNA. Whereas neutrophils release NUCLEAR DNA.
Eosinophil extracellular traps take just seconds
