Natural Born Killers: NK Cells and CD8+ T Lymphocytes Flashcards
What are the two types of immunity?
Innate: non-specific (or broadly specific), immediate response
Adaptive: highly-specific, delayed response
What is the role of cytotoxic lymphocytes?
We need cytotoxic cells as a means to destroy cells infected with bacteria, viruses or parasites and tumour cells.
This requires a cell-surface mechanism to display what is going on within a cell.
What antigens does MHC Class I present?
Proteins expressed within a cell (whether healthy, mutated or resulting from infection) are processed and presented on MHC Class I proteins.
As a recap, how are antigens from the cytosol presented on MHC I?
Protein from the cytosol will be ubiquinated to the proteosome (a unit specialised in recognising proteins from viruses) and be broken down into peptides.
These peptides will be imported into the ER via a transporter called TAP.
In the ER, we have the generation of the MHC I molecules. Here, it can try peptides from the virus; if it finds one that fits well, it stabilises and leaves, if not it is degraded.
When leaving, it does so through the Golgi into an exocytic vesicle that fuses with the plasma membrane.
On the surface, it presents its antigens to CD8+ T cells.
MHC class I proteins are central to anti-viral immune responses, so why don’t we see many pathogens that have mutated to avoid antigen presentation?
- we have multiple MHC genes (HLA-A, B and C)
- there is high genetic variability within these genes
How does MHC variation impact peptide binding?
By switching around the amino acids, you’ll get a different positive and negative charge on the protein, and the size and shape of the pockets in which the peptide sits in could also be affected.
This means different peptides binds to different MHCs due to the different alleles.
Describe the TCR recognition of the MHC?
TCR recognises both the MHC protein and the peptide antigen being presented by it.
It binds with a diagonal footprint that cuts across both alpha helices with the peptide in between.
How do pathogens adapt to stop being presented on MHC I?
- inhibit MHC-I transcription (adenovirus)
- block TAP activity (HSV)
- retain MHC-I in the endoplasmic reticulum (adenovirus, HCMV)
- target MHC-I for disposal from ER (HCMV)
- downregulate MHC-I from cell surface (HIV)
What are NK cells?
Classical NK cells are large granular lymphocytes that are not T or B cells.
They do not express T Cell Receptor (CD3) or B cell receptor.
They do express the cell surface marker CD56.
What are the two main functions of NK cells?
They have two main functions: cytokine secretion and killing targets.
Why are NK cells important to the up-regulation of immunity?
Medium and high cytolytic function was associated with reduced cancer risk; low cytolytic function was associated with increased cancer risk.
Low NK cell activity also correlates with severe disseminating herpesvirus infections.
What receptors are found on the surface of NK cells?
Killer Ig-like receptors (KIR) are innate immune receptors that regulate the activity of NK cells.
Leukocyte Ig-like receptors (LILR) are innate immune receptors that regulate the functions of NK cells.
KIR and LILR are encoded in a gene complex (the leukocyte receptor complex or LRC) on chromosome 19.
Describe the function of KIRs on NK cells.
When KIR recognise MHC-I, they inhibit NK cells from releasing lytic granules.
Some viruses down-regulate MHC-I as a means to evade cytotoxic T cells, and loss of MHC-I is also a common feature of tumour cells.
If a target cell does not express MHC-I then there is no KIR inhibition, so lytic granules will be released to lyse the target.
This is known as “missing self”.
Describe the function of NCRs on on NK cells.
NCRs are natural cytotoxicity receptors.
These provide activating signals to NK cells, but are not well characterised – we don’t know everything about them, they’re a bit of a mystery.
- NCR1 binds viral hemagglutinin.
- NCR2 binds a ligand that is expressed on tumour cells and upregulated by viral infection.
- The ligand for NCR3 is a stress induced protein.
How can antibodies activate NK cells?
Another (super) activator for NK cells is Fc receptors. This Fc receptor on the NK cell will see the antibodies, and because they will probably be packed together, that’s enough to crosslink and bring the activating receptors together.
That gives a very strong signal to the NK cell to destroy the target; this will outweigh a lot of inhibitory signals as it is a very strong stimulus.
