Natural Born Killers: NK Cells and CD8+ T Lymphocytes Flashcards
Describe the origin of NK cells and T-cells
Both arise from common lymphoid progenitor cell
Both part of the lymphocyte lineage
What is MHC-1 recognised by?
MHC-I = recognised by CD8+ cytotoxic T cells.
What is expressed on a MHC-1?
Proteins expressed within a cell (whether healthy, mutated or resulting from infection) are processed and presented on MHC class I proteins.
Describe the structure of an MHC-1 molecule
- Humans: HLA-A, -B, -C
- Tissue distribution: all nucleated cells
- two polypeptides, non-covalently bound
- alpha 3 domain and beta-2 macroglobulin provide support to peptide binding group at the top
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?
Multiple genes for MHC class I (e.g. two copies each of HLA-A, B and C)
High genetic variability within these genes
Where can alterations in the MHC molecule occur?
- Amino acids in the MHC peptide binding groove create pockets where the bound peptide can “anchor”
- Pockets where peptide binds- by substituting different amino acids changes +/- charges
- Size and shapes of pockets vary too
- Mutations tend to be In and around peptide binding group
Describe how a TCR binds to the MHC molecule
- Binds diagonally to contact MHC allele and the peptide antigen.
- Cutes across both alpha helices and the peptide between.
- Receptor interaction is not strong so CD8 acts as co-receptor and needed for effective response.
- TCR binds a1a2 region at top whilst CD8 binds the support domain a3 and b2-microglobulin. Similar for CD4 and MHCII
How might microbes influence the MHC molecule?
- Microbes may subvert MHC upregulation
- Inhibit MHC-I transcription (adenovirus)
- Blocks TAP activity (HSV)
- Retain MHC-I in endoplasmic reticulum (adenovirus, HCMV)
- Target MHC-I for disposal from ER (HCMV)
- Downregulate MHC-I from cell surface (HIV)
Describe what natural killer cells express and do not express
What do they produce?
- Do not express T Cell Receptor (CD3) or B cell receptor.
- Do express the cell surface marker CD56.
- Have cytotoxic function and cytokine secretion.
- Seen at site of contact in pregnancy (placenta) to secrete INF-y.
- Those found in blood are specialised for killing- cytotoxic.
- More active the NK, lower the risk of cancer. Less active, more viral infections.
What are Killer Ig-like receptors (KIR)?
What are Leukocyte Ig-like receptors (LILR)?
What are these receptors encoded by?
- Killer Ig-like receptors (KIR) are innate immune receptors that regulate the activity of Natural Killer 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
What is the function of Killer Ig-like receptors (KIR)?
- 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, 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, lytic granules will be released to lyse the target
- Known as “missing self”
- Inhibitory KIR bind to the same face of MHC-I as the T cell receptor
- recognise subsets of MHC-I alleles
- KIR are also polymorphic, as well as being polymorphic individual KIR genes vary in their presence between individuals
- Different MHC-I/KIR combinations show disease associations e.g. in HIV infection (eg Martin et al 2002 Nat Genet 31:429)
- Different chemoreceptors recognise different groups of MHC alleles
- Some specificity but not fins specificity
What are Natural cytotoxicity receptors (NCRs)?
What does NCR 1 bind?
What does NHR 2 bind?
- These provide activating signals to NK cells, but are not well characterised
- NCR 1 binds viral hemagglutinin
- NCR2 – binds a ligand that is expressed on tumor cells and upregulated by viral infection
- Ligand for NCR3 is a stress induced protein
What are the outcomes of the NK binding to a target cell?
- balance of inhibitory signal from recognising MHC and activating signal from other receptors controls NK activity
- if inhibitory receptor sees MHC target BUT no activating interaction then NK cell doesn’t kill
- if lost MHC and no negative signal but are getting activating signal then NK cell kills
- also if activating signals outweigh inhibitory signals then kill occurs (and vice versa)
Describe Antibody-dependent cell-mediated cytotoxicity (ADCC)
- FC receptors- activating signal for NK cells
- If infected cell with viral antigen on surface and already made antibod response to it that antibody will bind to it
- FC Receptor on NK cell will see antibody- because they are on cell closely packed together that is enough to cross link and bring activating receptor together and brings strong signal to NK to destroy target
- Outweighs inhibitory signals from MHC
Why do NK cells kill tumour cells?
- Similar to many pathogens, tumor cells can escape the adaptive immune system, by downregulating the expression of MHC class I.
- This makes them more susceptible to NK cells.
