Natural born killers Flashcards
What is innate immunity?
• Innate is relatively non-specific/broadly specific and immediate response
What is adaptive immunity?
• Adaptive is highly specific and theirs a delayed response
Where do both natural killer cells and T cells both originate from and so what are both?
Natural killer cells and T cells both originate from common lymphoid progenitor cells, so both are lymphocytes
What are cytotoxic cells used to destroy?
Cytotoxic cells are used to destroy our own cells that are infected with bacteria/viruses/parasites or tumour cells
Where are MHC class proteins found and what do they form?
MHC class proteins are found at the cell surface and form a structure that holds antigenic peptides for surveillance by T cells
What cells are MHC class I recognised by?
• MHC class I is recognised by CD8.+ cytotoxic T cells
What are all normal and viral proteins presented by?
• All normal proteins as well as viral proteins are presented by MHC class I
How do adenoviruses stop their peptides from getting presented on MHC class I?
§ Inhibit MHC-I transcription
How does HPV stop their peptides from getting presented on MHC class I?
§ Blocks TAP activity
□ This is the transporter which gets peptides from cytoplasm into ER
§ MHC-I remains empty
How does HCMV stop their peptides from getting presented on MHC class I?
§ Retains MHC-I in ER or targets MHC-I for disposal from ER
How does HIV stop their peptides from getting presented on MHC class I?
§ Downregulates MHC-I from cell surface
What structural domains does MHC class I have?
MHC class I has the structural domains alpha-3 and beta2 macroglobulin
What are the structural domains in MHC class I for?
○ Largely there to provide support to the peptide binding groove on top
What is MHC class I found on?
• MHC class I is found on every nucleated cell
What HLA do humans have?
• Humans have HLA-A, B or C
What are MHC class I proteins central to?
• MHC class I proteins are central to anti-viral immune responses
Where are polymorphisms found in the MHC protein and what does this decide?
• Polymorphisms are found in the upper peptide part of the MHC protein
§ This decides what peptides the MHC class can bind toWhat do amino acids in the MHC peptide groove create?
• Amino acids in the MHC peptide groove create pockets where the bound peptide can anchor
What do MHC class I and II play a central role in?
• MHC class I and II play a central role in the ability of the immune system to distinguish self from non-self
What are the 2 things TCR recognise?
• TCRs recognise 2 things:
○ The MHC protein itself
○ The antigenic peptide presented by the MHC protein
How does TCR bind with MHC protein and what does this help the TCR with?
• TCR binds with a diagonal footprint that cuts across both alpha helices with the peptide in between
○ This helps TCR to bind to both the MHC and the peptide
What is the interaction between the TCR and MHC-I and therefore what is used to make an effective response.
• For cytotoxic T cells, the interaction between the TCR and MHC-I isn’t very strong
○ Therefore use CD8 as a co-receptor to make an effective response
What domain does TCR bind to and where is it located?
• TCR binds to the alpha1alpha2 domains which is at the top of the MHC
What does CD8 bind to and what is the reason for?
• CD8 bind to the support domains at the bottom of the MHC
§ This is the reason for the lack of polymorphism at the bottom if the MHC, hence highly conserved
What are natural killer cells?
• Large granular lymphocytes that are not T/B cells
What do natural killer cells generally express?
• Generally express the cell surface marker CD56
What are the 2 major functions of natural killer cells?
- Cytokine secretion
2. Cytotoxic functions
What function was associated with reduced cancer risk?
• Medium and high cytolytic function was associated with reduced cancer risk whereas low cytolytic function was associated with increased cancer risk
What are killer Ig-like receptors(KIR)?
Killer Ig-like receptors(KIR) are innate immune receptors that regulate the activity of natural killer cells
What are leukocyte Ig-like receptors?
• Leukocyte Ig-like receptors(LILR) are innate immune receptors that regulate the functions of NK cells
What happens when a KIR recognises a MHC-I?
inhibits NK cells from releasing lytic granules
What do some viruses do to evade cytotoxic T cells?
• Some viruses down regulate MHC-I as a means to evade cytotoxic T cells
What is the loss of MHC-I a common feature of?
• Loss of MHC-I is also common feature of tumour cells
What happens to KIR if the target cell doesn’t express MHC-I and what does this cause?
• If a target cell doesn’t express MHC-I, then there’s no KIR inhibition
§ This causes lytic granules to be released to lyse the target
What does inhibitory KIR bind to the same face of as the T cell receptor?
• Inhibitory KIR bind to the same face of MHC-I as the T cell receptor
Why are KIR polymorphic?
• KIR are also polymorphic as KIR genes vary in their presence between individuals
What do different MHC-I/KIR combinations show?
• Different MHC-I/KIR combinations show disease associations
What do natural cytotoxicity receptors(NCR) provide?
• These provide activating signals to NK cells but are not well characterised
What does NCR 1 bind?
• NCR 1 binds viral haemagglutinin
What does NCR 2 bind?
• NCR 2 binds a ligand that is expressed in tumour cells and upregulated by viral infection
What does NCR 3 bind?
• NCR 3 binds a ligand that is stress induced
How can tumour cells escape the adaptive immune system and what does it make tumour cells more susceptible to?
• Tumour cells can escape the adaptive immune system by downregulating the expression of MHC class I § Become more susceptible to NK cells
What do NK cells and T cells carry?
• NK cells and T cells carry granules filled with cytotoxic proteins
At what site are cytotoxic granules containing released and what are they?
Release cytotoxic granules containing proteins at site of contact with target cells
- Perforin
- Granzymes
- Granulysin
What do perforins help deliver?
§ Helps deliver contents of granules into cytoplasm of target cells
What do granzymes activate?
§ Activate apoptosis once in cytoplasm of target cell
What does granulysin have and what can it induce?
§ Has antimicrobial properties and can induce apoptosis
Why must cytotoxic granules be directed?
• Must be directed in order to avoid damaging innocent bystander cells
What do CD8 cells trigger apoptosis of target cell through?
• CD8 cells can also trigger apoptosis of target through Fas/FasL interaction
Apoptotic pathway Fas/FasL interaction
○ FasL on T cell interacts with Fas protein on target cells
○ Binding trimerizes death domain on Fas protein
○ Interacts with Fas associated death domain(FADD)
○ FADD has a death effector domain(DED) which converts pro-caspase 8 to caspase 8
○ Triggers the extrinsic apoptotic pathway
What is Fas/FasL triggered apoptosis used to dispose?
• Fas/FasL triggered apoptosis is used to dispose of unwanted lymphocytes
What can loss of Fas result in?
• Loss of Fas can result in autoimmune lymphoproliferative syndrome(ALPS)
