Immunology: 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 cell type do both NK cells and T cells origibate from?
- Both arise from common lymphoid progenitor cells
- Both part of the lymphocyte lineage
Why do we need cytotoxic lymphocytes?
- We need cytotoxic cells as a means to destroy:
- Cells infected with bacteria, viruses or parasites
- Tumour cells
- Cytotoxic lymphocytes give immune system a way of knowing what is going on inside a cell just by looking at cell surface
What is MHC class I?
- Major histocompatibility (MHC) class I are proteins that are found at the cell surface and form a structure that holds antigenic peptides for surveillance by T cells
What immune system cell recognises MHC class I?
- Recognised by CD8+ cytotoxic T cells
What types of protein can get expressed by MHC class I?
- Proteins expressed within a cell (whether healthy, mutated or resulting from infection)
- NOT JUST VIRAL PROTEINS
How does viral infeaction of a cell lead to MHC class I antigen presentation and killing of the virally infected cell?
Describe the structure of MHC class I
- Two polypeptides, non-covalently bound
- α3 and β2-microglobulin provide support to the peptide binding cleft
- α1 and α2 make up the peptide binding cleft
- In humans there are 3 MHC class I genes: HLA-A, -B, -C
- Tissue distribution: all nucleated 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?
- There are multiple MHC class I genes - we also inherit two copies of each of these genes
- High genetic variability within these genes
What part of MHC class I proteins do the majority of MHC polymorphisms (mutations) affect?
- Polymorphisms affect the upper peptide-binding part of the MHC protein
How does genetic variation in MHC class I affect peptide binding?
- Amino acids in the MHC peptide binding groove create pockets where the bound peptide can “anchor”
- These amnio acids have positive/negative charges so by switching these amino acids you get different positive and neagtive charges on the protein
- This changes the size and shape of the pockets in the peptide binding groove which means different peptides bind to different MHC class I alleles
How does the T-cell receptor (TCR) recognise MHC class I when binding?
- TCR recognise two things:
- MHC protein itself
- Antigenic peptide presented by MHC protein
How does the T-cell receptor orientate itself when binding to MHC class I?
- TCR Binds with a diagonal footprint that cuts across both alpha helices of the peptide binding cleft and the antigenic peptide in between
What role does CD8 play in TCR binding to MHC class I?
- CD8 acts as a co-receptor for MHC-I, and is required for the T cell to make an effective response - strengthens interaction between TCR and MHC class I
- TCR binds to the α1 and α2 domains
- CD8 binds to the support domains (α3 and β2-microglobulin)
- Similar situation for CD4 and MHC-II
How do pathogens subvert MHC class I upregulation?
- Inhibit MHC-I transcription (adenovirus)
- Block TAP (Transporter associatd with antigen processing) activity - TAP brings antigens in cytosol to ER (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 the 2 amin receptors found on NK cells and what do they do?
- Killer Ig-like receptors (KIR) - Innate immune receptors that regulate the activity of Natural Killer cells
- Leukocyte Ig-like receptors (LILR) - Innate immune receptors that regulate the functions of NK cells
Explain the activity of killer Ig-like receptors
- When KIRs recognise MHC class I they inhibit NK cells from releasing lytic granules
- If a target cell does not express MHC class I then KIR unable to bind meaning there’s no inhibition signal
- This causes NK cell to release lytic granules to lyse the target
- This is known as “Loss of self” or “missing self”
How do Killer Ig-like receptors bind to MHC class I?
- KIR binds to the same face of MHC-I as the T cell receptor - binds to edge of peptide binding cleft unlike TCR which binds to entire cleft in a diagonal manner
- Recognise subsets of MHC-I alleles
What are soem other characteristics of Kiler Ig-like receptors?
- Polymorphic
- Individual KIR genes vary in their presence between individuals
- Different classes of KIR show some MHC class I specificity but not to same extent as TCR
What are the 3 types of natural cytotoxicity receptors (NCRs)?
- NCRs provide activating signals to NK cells
- 3 types:
- NCR 1 - binds viral hemagglutinin
- NCR 2 – binds a ligand that is expressed on tumor cells and upregulated by viral infection
- NCR 3 - binds is a stress induced protein
What controls that activity of NK cells?
- Balance between activating signals, NCRs, and inhibitory signals, KIRs, when recognising MHC class I
Explain how an antibody can activate an NK cell
- Infected cell with viral antigens on its surface is bound to by virus-specific antibodies
- Fc region on antibodies bind to Fc receptors on NK cells
- This leads to cross-linking of the Fc receptors which results in activation of the NK cells
- Activation of NK cell leads to infected cell dying via apoptosis
- NOTE: Binding of Fc region of antibody to Fc recptor on NK cell can override inhibitory signal of MHC class I binding by KIR of NK cell
Why are NK cells able to 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 recognition via NK cells
How do NK cells and cytotoxic T cells kill infected cells?
- NK cells and Cytotoxic T cells carry granules filled with cytotoxic proteins, e.g. Perforin
- Release cytotoxic granules at site of contact with target cell
- Must be directed in order to avoid damaging innocent bystander cells
Apart from Cytotoxic granules how else can Cytotoxic T cells kill infected cells?
- Fas ligand (FasL) on T cells binds to and trimerizes Fas on target cells to trigger apoptotic pathway
- This trimerisation of Fas causes clustering of death domains on Fas protein
- This causes FADD to interact with death domains of the Fas protien
- FADD has death effector domain (DED) which converts pro-caspase 8 to caspase 8
- Caspase 8 triggers apoptosis
* NOTE: Fas/FasL triggered apoptosis is used to dispose of unwanted lymphocytes
What can loos of Fas protein on cells lead to?
- Loss of Fas can result in autoimmune lymphoproliferative syndrome (ALPS)
Compare and contrast receptor type, ligand type and activity in presence and absence of MHC class I for cytotoxic T cells and NK cells
Compare and contrast some other characteristics of cytotoxic T cells and NK cells
