Natural Killer and Cytotoxic T Cells

Question 1

What is the difference between innate and adaptive immune responses?

Answer 1

➝ innate : non-specific, immediate response

➝ Adaptive : highly-specific, delayed

Question 2

Where do NK and T cells arise from?

Answer 2

➝ common lymphoid progenitor

Question 3

What kind of cells are NK cells?

Answer 3

➝ innate lymphoid cells

Question 4

What is the role of cytotoxic lymphocytes?

Answer 4

➝ kill cells infected with bacteria, viruses or parasites

➝ kill tumor cells

Question 5

Where are MHC proteins found and what do they do?

Answer 5

➝ at the cell surface

➝ form a structure that holds antigenic peptides for surveillance

Question 6

What cell is MHC I recognised by?

Answer 6

➝ CD8+ cytotoxic T cells

Question 7

What proteins does MHC I present?

Answer 7

➝ ALl proteins including normal cellular proteins and not just viral

Question 8

How is does MHC present intracellular proteins?

Answer 8

➝ they are cleaved by the proteasome
➝ transported into the ER
➝ bind to MHC I
➝ transported to the cell surface

Question 9

How does an infected cell get killed by CD8+ T cells?

Answer 9

➝ 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

Question 10

What is the structure of MHC class I?

Answer 10

➝ Two polypeptides not covalently bound

➝ alpha 3 domain and beta 2 microglobulin are there to provide support to the peptide binding groove

Question 11

Why haven’t pathogens mutated to avoid MHC presentation?

Answer 11

➝ There are multiple genes of MHC class I 
➝ high genetic variability within these genes

Question 12

Where are the polymorphisms found in MHC?

Answer 12

➝ Upper peptide binding part

Question 13

How can different peptides bind?

Answer 13

➝ Different amino acids from different alleles means different charges and size and shape of the peptide binding groove

Question 14

What two things do T cells recognise?

Answer 14

➝ MHC protein

➝ antigenic peptide presented by MHC

Question 15

How does the TCR bind to MHC and why?

Answer 15

➝ 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

Question 16

Why are co-receptors needed when a cytotoxic T cell interacts with MHC?

Answer 16

➝ the interaction is not particularly strong

Question 17

What acts as a co-receptor with cytotoxic T cells?

Answer 17

➝ CD8

Question 18

What does the TCR and CD8 bind to?

Answer 18

➝ TCR binds to the alpha1 and alpha 2 domains

➝ CD8 binds to the support domains alpha 3 and beta 2M

Question 19

What parts of the MHC is conserved and what part has polymorphisms?

Answer 19

➝ The structural part that binds to CD8 is highly conserved

➝ the part that surrounds the peptide has polymorphisms

Question 20

Why is the structural part of the MHC highly conserved?

Answer 20

➝ the CD8 will not recognise it if it varies

Question 21

What are 5 ways that pathogens affect MHC and give examples of which viruses use these methods?

Answer 21

➝ 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

Question 22

What are classical NK cells?

Answer 22

➝ large granular lymphocytes that are not T or B cells

Question 23

What marker do NK cells express?

Answer 23

➝CD56

Question 24

How can you find NK cells under a microscope?

Answer 24

➝ they do not express TCR or CD3

Question 25

What does low NK activity correlate with?

Answer 25

➝ severe disseminating herpesvirus infections

Question 26

What does an NK deficiency lead to?

Answer 26

➝ severe viral infections early in life

Question 27

What are killer Ig-like receptors?

Answer 27

➝ Innate immune receptors that regulate the activity of NK cells

Question 28

What are leukocyte Ig-like receptors?

Answer 28

➝ Innate immune receptors that regulate the functions of NK cells

Question 29

What are KIR and LILR encoded by?

Answer 29

➝ leukocyte receptor complex | ➝ on chromosome 19

Question 30

What is the function of KIR (killer Ig like receptors)?

Answer 30

➝ when KIR recognise MHC I they inhibit NK cells from releasing lytic granules

Question 31

What is a common feature of tumor cells?

Answer 31

➝ loss of MHC I

Question 32

What happens if a target cell does not express MHC I and what is this known as ?

Answer 32

➝ no KIR inhibition ➝ lytic granules will be released ➝ missing self

Question 33

Where do inhibitory KIR bind?

Answer 33

➝ the same face of MHC I as the T cell receptor

Question 34

What do inhibitory KIR recognise?

Answer 34

➝ subsets of MHC I alleles

Question 35

What are NCRs?

Answer 35

➝ Natural cytotoxicity receptors

Question 36

What is the function of NCRs?

Answer 36

➝ provide activating signals to NK cells

Question 37

What does NCR1 bind to?

Answer 37

➝ Haemagglutinin

Question 38

What does NCR2 bind to?

Answer 38

➝ binds a ligand that is expressed on tumor cells and upregulated by viral infection

Question 39

What is the ligand for NCR3?

Answer 39

➝ stress induced protein

Question 40

What does target cell death or survival depend on?

Answer 40

➝ balance of activating and inhibitory signals

Question 41

What is ADCC?

Answer 41

➝ antibody dependent cell-mediated cytotoxicity

Question 42

How does ADCC?

Answer 42

➝ 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

Question 43

Why do NK cells kill tumor cells?

Answer 43

➝ they downregulate MHC

Question 44

How do NK and T cells lyse infected cells?

Answer 44

➝ they carry granules filled with cytotoxic proteins | ➝ they release the granules at the site of contact with the target cell

Question 45

What does perforin do?

Answer 45

➝ Aids in delivering contents of granules into the cytoplasm of the target cell

Question 46

What are granzymes?

Answer 46

➝ Serine proteases which activate apoptosis once in the cytoplasm of the target cell

Question 47

What is granulysin?

Answer 47

➝ Has antimicrobial actions and can induce apoptosis

Question 48

How is the CD8 apoptotic pathway triggered?

Answer 48

➝ the Fas ligand on T cells engages Fas on target cells to trigger the apoptotic pathway

Question 49

What is Fas/FasL triggered apoptosis used for?

Answer 49

➝ used to dispose of unwanted lymphocytes

Question 50

What can loss of Fas result in?

Answer 50

➝ Autoimmune lymphoproliferative syndrome ALPS

Question 51

Describe how the Fas ligand causes apoptosis?

Answer 51

➝ 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

Question 52

What does absence of MHC class I do to NK cells and cytotoxic T cells?

Answer 52

➝ NK : missing self - cytotoxicity | ➝ Cytotoxic T : lack of recognition

Question 53

What does presence of MHC class I do to NK cells and cytotoxic T cells?

Answer 53

➝ NK : Inhibitory signal to NK | ➝ Cytotoxic : TCR engagement

Question 54

What is the ligand for NK cells and cytotoxic T cells?

Answer 54

``` ➝ NK : class I MHC, MICA/B, immune complexes ➝ Cytotoxic : peptide-MHC class I complex ```

Question 55

What is the difference between cytotoxic T cell and NK receptors?

Answer 55

➝ 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

Question 56

What is the difference between how cytotoxic T cells and NK cells respond to MHC class I?

Answer 56

``` ➝ Cytotoxic : survey MHC class I on the surface of other cells, searching for foreign antigens ➝ NK : respond to an absence of MHC class I ```

Question 57

What is the difference in activation between cytotoxic T cells and NK cells?

Answer 57

➝ Cytotoxic : Initial activation of naive T cells, followed differentiation and proliferation required ➝ NK : ready to act on encountering targets in the periphery

Question 58

What is the difference in co-receptors between cytotoxic T cells and NK cells?

Answer 58

``` ➝ 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 ```

Question 59

What is the difference in memory between cytotoxic T cells and NK cells?

Answer 59

➝ Cytotoxic : memory | ➝ NK cells : no memory