Natural Killer and Cytotoxic T Cells Flashcards
What is the difference between innate and adaptive immune responses?
➝ innate : non-specific, immediate response
➝ Adaptive : highly-specific, delayed
Where do NK and T cells arise from?
➝ common lymphoid progenitor
What kind of cells are NK cells?
➝ innate lymphoid cells
What is the role of cytotoxic lymphocytes?
➝ kill cells infected with bacteria, viruses or parasites
➝ kill tumor cells
Where are MHC proteins found and what do they do?
➝ at the cell surface
➝ form a structure that holds antigenic peptides for surveillance
What cell is MHC I recognised by?
➝ CD8+ cytotoxic T cells
What proteins does MHC I present?
➝ ALl proteins including normal cellular proteins and not just viral
How is does MHC present intracellular proteins?
➝ they are cleaved by the proteasome
➝ transported into the ER
➝ bind to MHC I
➝ transported to the cell surface
How does an infected cell get killed by CD8+ T cells?
➝ viruses infect cells
➝ viral proteins are synthesized in the cytoplasm
➝ peptide fragments are bound to MHC class I
➝ MHC presents the viral peptides to the surface
➝ Cytotoxic T cells recognise viral peptides and kill the infected cells
What is the structure of MHC class I?
➝ Two polypeptides not covalently bound
➝ alpha 3 domain and beta 2 microglobulin are there to provide support to the peptide binding groove
Why haven’t pathogens mutated to avoid MHC presentation?
➝ There are multiple genes of MHC class I ➝ high genetic variability within these genes
Where are the polymorphisms found in MHC?
➝ Upper peptide binding part
How can different peptides bind?
➝ Different amino acids from different alleles means different charges and size and shape of the peptide binding groove
What two things do T cells recognise?
➝ MHC protein
➝ antigenic peptide presented by MHC
How does the TCR bind to MHC and why?
➝ with a diagonal footprint that cuts across both alpha helices with the peptide inbetween
➝ it allows it to make contact with the MHC and the peptide in the middle
Why are co-receptors needed when a cytotoxic T cell interacts with MHC?
➝ the interaction is not particularly strong
What acts as a co-receptor with cytotoxic T cells?
➝ CD8
What does the TCR and CD8 bind to?
➝ TCR binds to the alpha1 and alpha 2 domains
➝ CD8 binds to the support domains alpha 3 and beta 2M
What parts of the MHC is conserved and what part has polymorphisms?
➝ The structural part that binds to CD8 is highly conserved
➝ the part that surrounds the peptide has polymorphisms
Why is the structural part of the MHC highly conserved?
➝ the CD8 will not recognise it if it varies
What are 5 ways that pathogens affect MHC and give examples of which viruses use these methods?
➝ Inhibit MHC-I transcription - adenovirus
➝ Block TAP (HSV)
➝ Retain MHC-I in the ER (HCMV, adenovirus)
➝ Target MHC for disposal ( HCMV)
➝ Downregulate MHC-I from surface - HIV
What are classical NK cells?
➝ large granular lymphocytes that are not T or B cells
What marker do NK cells express?
➝CD56
How can you find NK cells under a microscope?
➝ they do not express TCR or CD3
What does low NK activity correlate with?
➝ severe disseminating herpesvirus infections
What does an NK deficiency lead to?
➝ severe viral infections early in life
What are killer Ig-like receptors?
➝ Innate immune receptors that regulate the activity of NK cells
What are leukocyte Ig-like receptors?
➝ Innate immune receptors that regulate the functions of NK cells
What are KIR and LILR encoded by?
➝ leukocyte receptor complex
➝ on chromosome 19
What is the function of KIR (killer Ig like receptors)?
➝ when KIR recognise MHC I they inhibit NK cells from releasing lytic granules
What is a common feature of tumor cells?
➝ loss of MHC I
What happens if a target cell does not express MHC I and what is this known as ?
➝ no KIR inhibition
➝ lytic granules will be released
➝ missing self
Where do inhibitory KIR bind?
➝ the same face of MHC I as the T cell receptor
What do inhibitory KIR recognise?
➝ subsets of MHC I alleles
What are NCRs?
➝ Natural cytotoxicity receptors
What is the function of NCRs?
➝ provide activating signals to NK cells
What does NCR1 bind to?
➝ Haemagglutinin
What does NCR2 bind to?
➝ binds a ligand that is expressed on tumor cells and upregulated by viral infection
What is the ligand for NCR3?
➝ stress induced protein
What does target cell death or survival depend on?
➝ balance of activating and inhibitory signals
What is ADCC?
➝ antibody dependent cell-mediated cytotoxicity
How does ADCC?
➝ Antibody binds antigens on the surface of target cells
➝ Fc receptors on NK cells recognise bound antibody
➝ Cross linking of Fc receptors signals the NK cell to kill the target cell
➝ Target cell dies by apoptosis
Why do NK cells kill tumor cells?
➝ they downregulate MHC
How do NK and T cells lyse infected cells?
➝ they carry granules filled with cytotoxic proteins
➝ they release the granules at the site of contact with the target cell
What does perforin do?
➝ Aids in delivering contents of granules into the cytoplasm of the target cell
What are granzymes?
➝ Serine proteases which activate apoptosis once in the cytoplasm of the target cell
What is granulysin?
➝ Has antimicrobial actions and can induce apoptosis
How is the CD8 apoptotic pathway triggered?
➝ the Fas ligand on T cells engages Fas on target cells to trigger the apoptotic pathway
What is Fas/FasL triggered apoptosis used for?
➝ used to dispose of unwanted lymphocytes
What can loss of Fas result in?
➝ Autoimmune lymphoproliferative syndrome ALPS
Describe how the Fas ligand causes apoptosis?
➝ Trimeric Fas ligand (FasL) binds to and trimerizes Fas
➝ Clustering of death domains in the Fas cytoplasmic domains allows Fas to recruit FADD vida its death domain
➝ The clustered death effector domains of FADD recruit pro-caspase 8 via similar DEDs in the pro-caspase
What does absence of MHC class I do to NK cells and cytotoxic T cells?
➝ NK : missing self - cytotoxicity
➝ Cytotoxic T : lack of recognition
What does presence of MHC class I do to NK cells and cytotoxic T cells?
➝ NK : Inhibitory signal to NK
➝ Cytotoxic : TCR engagement
What is the ligand for NK cells and cytotoxic T cells?
➝ NK : class I MHC, MICA/B, immune complexes ➝ Cytotoxic : peptide-MHC class I complex
What is the difference between cytotoxic T cell and NK receptors?
➝ Cytotoxic : each express a unique receptor with high specificity for a single MHC/peptide complex
➝ NK : Invariant receptor with broader specificity for MHC allele subsets
What is the difference between how cytotoxic T cells and NK cells respond to MHC class I?
➝ Cytotoxic : survey MHC class I on the surface of other cells, searching for foreign antigens ➝ NK : respond to an absence of MHC class I
What is the difference in activation between cytotoxic T cells and NK cells?
➝ Cytotoxic : Initial activation of naive T cells, followed differentiation and proliferation required
➝ NK : ready to act on encountering targets in the periphery
What is the difference in co-receptors between cytotoxic T cells and NK cells?
➝ Cytotoxic : use CD8 as a co-receptor for MHC class I ➝ NK : do not use a co-receptors for MHC class I. and do not express CD8
What is the difference in memory between cytotoxic T cells and NK cells?
➝ Cytotoxic : memory
➝ NK cells : no memory
