Natural Born Killers: NK Cells and CD8+ T Lymphocytes Flashcards
Describe the origin of NK and T cells
- Both arise from common lymphoid progenitor cell
- Both part of the lymphocyte lineage
What is the role of cytotoxic lymphocytes
- Need it to be able to destroy: infected cells and tumour cells
- Lymphocytes scanning a target cell surface need to detect changes in protein production inside that target cell
What are the key functions of Cytotoxic T cells
- Cytotoxic adaptive immune cells
- Kill virally infected targets
- Kill tumour cells
- Controlled by T cell receptor recognition, with CD8 acting as a co-receptor
- Highly specific
What are the key functions of Natural killer cells
- Cytotoxic innate immune cells
- Kill virally infected targets
- Kill tumour cells
- Controlled by a balance of signals between different activating and inhibitory receptors on their surface
- Broad specificity for target cells
Why do we need more than one type of cytotoxic lymphocyte
- To combat infection in the period before a T cell response develops
- To provide an alternative system when a tumour or infected cells evade Cytotoxic T cell responses
- To provide an additional mechanism for killing infected targets via antibody recognition
What are some consequences of low NK cells
Correlates with severe disseminating herpesvirus infections
Describe the role of MHC class 1
- Lymphocytes scanning a target cell surface need to detect changes in protein production inside that target cell
- MHC class I proteins are found at the cell surface
- Form a structure that presents protein fragments (peptides) at the cell surface for immune surveillance
- Recognised by CD8+ cytotoxic T cells
How are intercellular protein presented on MHC class 1
- Proteins are processed in the proteasome and enter the endoplasmic reticulum.
- Binds with MHC 1 at the ER and makes its way to the cell surface to be presented
Describe the structure of MHC class 1
- Peptide binding cleft where the peptide fragments are bound
- “Hot dog bun structure”
Why do we have highly polymorphic HLA
- Pathogens can evolve to evade immune responses
- Variation in MHC class I proteins - Multiple genes (e.g. two copies each of HLA-A, B and C) and high genetic variability within these genes may counteract this across populations
What is the result of MHC polymorphism
- Variance seen in the upper peptide binding groove
- Many different pockets and differences in charges and size of binding region
- Variance in peptides that can anchor within pockets
How does TCR bind MHC class 1
- TCR recognises both the
MHC protein and the
peptide antigen being
presented by it - Binds with a diagonal
footprint that cuts across
both alpha helices with
the peptide in between
what is the role of CD8 in MHC class 1 binding
- CD8 acts as a co-receptor for MHC-I, and is required for the T cell to make an effective response
- TCR binds to the a1a2 domains
- CD8 binds to the support domains (a3 and b2m)
How can pathogens subvert MHC-1 presentation
- Inhibit MHC-I transcription (adenovirus)
- Block peptide transport into the endoplasmic reticulum (HSV)
- Retain MHC-I in endoplasmic reticulum (adenovirus, HCMV)
- Target MHC-I for disposal from the endoplasmic reticulum (HCMV)
- Downregulate MHC-I from cell surface (HIV)
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
- This mechanism is known as “missing self”
How does KIR bind to TCR
- 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
What are natural cytotoxicity receptors
- These provide activating signals to NK cells, but their range of ligands is not well characterised
- NKp46 is known to bind viral hemagglutinin
- NKp44 – binds a ligand that is expressed on tumour cells and upregulated by viral infection
- Ligand for NKp30 is a stress-induced protein
What does target cell death depend on
- Balance of activating or inhibitory signals
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.
Describe the recognition of antibody-dependant cell-mediated complexes
- NK cells express a receptor that recognizes the Fc portion of antibodies
- This receptor delivers a strong activating signal when it recognizes antibodies bound to a cell surface
- Results in lysis of the target cell
How does cytotoxic granules carry out lysis
- NK cells and T cells carry granules filled with
cytotoxic proteins - Release cytotoxic granules at the site of contact with
target cell - (must be directed in order to avoid damaging
innocent bystander cells)
Describe the immunological synapse
- T cell receptors and co-receptors cluster at the site of cell-cell contact
- This polarises the T cell to release effector molecules at the point of contact
How does Fas/FasL interaction cause apoptosis
- This process is slower than cytotoxic granules (2 hour lag time)
- Fas ligand (FasL) on T cells engages Fas on target cells to trigger apoptotic pathway
- Fas/FasL triggered apoptosis is used to dispose of unwanted lymphocytes
- Loss of Fas can result in autoimmune lymphoproliferative syndrome (ALPS)