Natural Born Killers: NK Cells and CD8+ T Lymphocytes Flashcards
How are CD8 T cells and NK cells similar?
Both Cytotoxic T cells and natural killer cells essentially do the same job but as part of different types of immunity
Which cell is a major part of the innate immune system?
NK cells: non-specific (or broadly specific), immediate response
Which immune cell is an integral part of the adaptive immune system?
T cells: highly-specific, delayed response`
Where do T cells and NK cells originate?
Both arise from common lymphoid progenitor cell
Both part of lymphocyte lineage
What is the role of cytotoxic CD8+ T cells?
We need cytotoxic cells as a means to destroy
- Cells infected with bacteria, viruses or parasites
- Tumour cells
What is the role of MHC Class I molecules?
MHC class I proteins are found at the cell surface and form a structure that holds antigenic peptides for surveillance by T cells
How are MHC I molecules recognised?
MHC-I = recognised by CD8+ cytotoxic T cells
How do MHC molecules aid pathogen recognition?
Intracellular proteins are presented at the cell surface by MHC class I
Which proteins are presented on MHC I molecules?
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 MHC I molecules
Humans: HLA-A, -B, -Ctwo polypeptides, non-covalently bound:
𝛂3 domain and ꞵ2 microglobulin provide support to peptide binding group on top
2 𝛂 helices at sides of groove and ꞵ sheet at the bottom forms base
Which cells express MHC Class I molecules?
all nucleated cells
Why don’t we see many pathogens mutating to avoid antigen presentation
MHC class I proteins are central to antiviral immune responses
- Multiple genes (e.g. 2 copies each of HLA-A, B + C)
- High genetic variability within these genes
Outline what enables MHC Class I variability
Polymorphisms in upper peptide-binding part of MHC protein - provide variation in the peptide binding groove
Where on the MHC molecule do pathogenic peptides bind?
Amino acids in the MHC peptide binding groove create pockets where the bound peptide can “anchor”
How do polymorphisms provide variation in MHC I molecules?
By substituting different amino acids, we get different charges (+ve/-ve) between MHCs, different sizes and shapes between pockets ⇒ different peptides bind to different MHC alleles
What substances do TCRs recognise?
TCR recognise two things
- MHC protein itself (hence compatibility)
- Antigenic peptide presented by MHC protein
TCR recognises both MHC protein and peptide antigen being presented by it
How does MHC structure allow T cel recognition?
Binds with a diagonal footprint that cuts across both alpha helices with the peptide in between - allows T cell recognition
WHy can CD8 and TCRs bind to MHC simultaneously?
Distant binding sites allow CD8 and TCR to bind MHC-I at the same time
What is the role of CD8 binding to MHC?
CD8 acts as a co-receptor for MHC-I, and is required for the T cell to make an effective response
Where on the MHC I molecule do TCRs bind?
TCR binds to the α1α2 domains
Which part of the MHC I molecule do CD8 peptides bind?
CD8 binds to the support domains (α3 and β2m) - very highly conserved region to ensure CD8 binding
- Similar situation for CD4 and MHC-II
Outline how different viruses may subvert MHC functions
Microbes may subvert MHC upregulation by:
- Inhibit MHC-I transcription (adenovirus)
- Block 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)
What are NK cells?
Classical NK cells are large granular lymphocytes that are not T or B cells
Describe the protein structures of classic NK cells
- Don’t express TCR (CD3) or B cell receptor
- Express cell surface marker CD56
- CD3- CD56+
What are the 2 major roles of NK cells
Cytotoxic functions and cytokine secretion
There are different populations of NK specialised more towards either function
Most are specialised for cytotoxic functions
How do MHC I molecules recognise NK cells?
Killer Ig-like receptors (KIR) are innate immune receptors that regulate the activity of Natural Killer cells - their binding site is within the antigen presenting part of the MHC
What is the function of KIR?
When KIR recognise MHC-I they inhibit NK cells from releasing lytic granules (-ve signal)
Why do KIR inhibit NK cytotoxic functions?
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
Mechanism also protects healthy cells
How odes a lack of MHC I molecules enable NK cytotoxic effects?
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”
Where do KIR bind n MHC?
Inhibitory KIR bind to the same face of MHC-I as the T cell receptor
- recognise subsets of MHC-I alleles
Describe the variation in KIR
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 is the role of natural Cytotoxicity receptors on NK cells?
These provide activating signals to NK cells, but are not well characterised (+ve signal)
Describe the roles of different NCRs
NCR 1 binds viral hemagglutinin
NCR2 – binds a ligand expressed on tumor cells and upregulated by viral infection
Ligand for NCR3 is a stress induced protein
How is NK Cell activity regulated?
NK cell activity is regulated by a balance between inhibitory signals (recognising MHCs) and activating signals from other receptors
What is ADCC?
Antibody-Dependent Cell-Mediated Cytotoxicity is a Super activating signal for NK cells
- Fc receptors (CD16)
Outline how Fc receptors on NK cells activate a lytic response
- Antibodies bind antigens on target cell surface
- Fc receptors on NK cells recognise bound antibodies
- Cross-linking of Fc receptrs signals NK cell to kill target cell
- Target cell dies by apoptosis
How do Tumour cells evade immune responses?
Similar to many pathogens, tumor cells can escape the adaptive immune system, by downregulating the expression of MHC class I
- makes them more susceptible to NK cells
How do cytotoxic (T + NK) cells kill target cells?
NK cells and T cells carry granules filled with cytotoxic proteins
Release cytotoxic granules at site of contact with target cell
(must be directed in order to avoid damaging innocent bystander cells)
Name 3 cytotoxic granules in CD8 T cells
- Perforin
- Granzymes
- Granulysin
What is the role of perforin?
Delivers contents of granules into cytoplasm of target cell
How do granzymes cause cytotoxic effects?
Serine proteases
Activate apoptosis once inside target cell cytoplasm
How does granulysin activate apoptosis?
Antimicrobial action causes apoptosis
How do CD8 cells trigger apoptosis?
CD8 cells can trigger apoptosis of target through Fas/FasL protein interaction
- not cytotoxic granule dependent
Describe the Fas/FasL interaction
Fas ligand (FasL) on T cells engages Fas on target cells to trigger apoptotic pathway
What is the use of Fas/FasL apoptosis?
Fas/FasL triggered apoptosis is used to dispose of unwanted lymphocytes
What is the consequence of loss of Fas?
Loss of Fas can result in autoimmune lymphoproliferative syndrome (ALPS) due to lack of removal of excess lymphocytes
