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Microbiology & Immunity > 25- Natural Born Killers: NK cells (and CD8+ T cells) > Flashcards

25- Natural Born Killers: NK cells (and CD8+ T cells) Flashcards

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Biology 101 flashcards
1
Q

what is the role of cytotoxic lymphocytes?

A

detect and destroy
- self/host cells infected with bacteria, viruses or parasites
- tumour cells making tumour proteins

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2
Q

what are CD8+ T cells part of? how do they work?

A

cytotoxic cells, part of the adaptive immune system

controlled by TCR recognition with CD8 co-receptor - TCR binds to antigen-MHC complex with high specificity, CD8 co-receptor stabilises interaction

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3
Q

what are NK cells part of? how do they work?

A

cytotoxic cells, part of innate immune system

controlled by a balance of signals between different activating and inhibitory receptors on their surface = determines whether they kill

kills virally infected cells and tumour cells - had broad specificity for target cells, recognises multiple different antigens

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4
Q

why do we need more than one type of cytotoxic lymphocyte?

A
  1. combat infection in the period before a T cell response develops
    - it takes approx. 7 days for an adaptive T cell response to develop, 3-4 days for NK cell responses
    - can bringdown the viral load whilst the adaptive response develops
  2. provide an alternative system when tumour/ infected cells evade cytotoxic T cell responses
    - NK cells are back up cells
  3. provide an additional mechanism for killing infected targets via antibody recognition
    - NK cells can interact with antibodies
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5
Q

what is the link between NK activity and cancer?

A

low NK activity – can be caused by genetic mutations

higher susceptibility for viral infections – esp. herpes virus infections, chickenpox

higher chance of developing cancer

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6
Q

what MHC class do CD8+ T cells bind?

A

MHC class 1

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7
Q

where is MHC class 1 present? what do they present?

A

on all nucleated cells, not RBCs

present intracellular proteins - self/ mutated/ pathogenic/ tumour

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8
Q

describe the processing of intracellular proteins for MHC class 1 presentation

A

intracellular protein contained with proteasome - a multi-protein complex

peptide is chopped up into smaller peptide fragments - taken to ER

peptide fragments encounter unoccupied MHC class 1 - peptide-MHC 1 bind

complex translocates to cell surface via secretory pathway for CD8+ T cell detection

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9
Q

describe the structure of MHC class 1

A

peptide binding groove at the top made up of two large polypeptide chains:
- two alpha helices at the edges of PBG - make up boundaries/ sides of the groove
- beta pleated sheet as the base/ platform of PBG

large alpha chain at the bottom of PBG and beta2microglobulin at the lower part of MHC structure = structural support

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10
Q

describe the genetic polymorphisms of MHC class 1 - genetic organisation of MHC genes?

A

organisation - MHC class 1 & 2 proteins encoded on chromosome 6 within MHC gene complex
- three genes for MHC 1 (HLA-A, B, C), three for MHC 2 (HLA- DQ, DR, DP)
- two copies of each chromosome = 6 genes each for each MHC

highly polymorphic - 1000s of polymorphisms that affect the peptide protein groove

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11
Q

what genes encode MHC 1?

A

HLA A, B C = three genes

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12
Q

what genes encode MHC 2?

A

HLA- DQ, DR, DP = three genes on one chromosome

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13
Q

what’s the importance of MHC class 1 polymorphism?

A

pathogens evolve through replication and transmission to evade immune responses, increase virulence/ pathogenicity

high MHC genetic polymorphism allows generation of immune system/ immunity within a population to fight off pathogens even as they evolve

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14
Q

how do MHC class 1 genetic polymorphisms affect its structure?

A

affects peptide binding groove of MHC 1 - affect:
- size
- shape of PBG ‘pockets’/ peptide binding domains antigenic peptide amino acids anchor into
- electric charge of pockets

changes determine what (variant of an) antigenic peptide can be bound by a particular MHC 1 molecule - peptide MHC1 binding is very specific

variations between different MHC alleles = variations in size, charge and location of pockets = variations in peptides that can anchor within the pockets

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15
Q

what two things can TCRs detect?

A

MHC protein - is it self/ non-self MHC
antigenic peptide presented by MHC

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16
Q

how do CD8+ T cells bind to MHC1-peptide complex? - TCR and CD8+ receptor bindings? importance?

A

TCR binds diagonally across MHC1 (alpha 1 & 2)= covers top of alpha helices and PBG
- ensures TCR is in contact with MHC1 molecule and antigenic peptide to determine if they’re self or foreign

CD8+ co-receptor binds the lower, conserved region of MHC 1 (alpha 3 and beta2microglobulin)
- doesn’t interfere with TCR binding sites
- structural support, stabilises TCR-MHC1-peptide interactions

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17
Q

at what domains does TCR bind to presented MHC1-peptide?

A

alpha 1 and 2 domains

binds diagonally across alpha helices and top of PBG

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18
Q

at what domains does CD8+ co-receptor bind to presented MHC1-peptide?

A

alpha 3 and beta2microglobulin (lower, conserved regions)

19
Q

describe CD8+ TCR, MHC 1 and peptide interactions

A

TCR determines if the MHC1 molecule is self, and if the antigenic peptide presented is self

TCR specificity detects the specific MHC1-peptide complex and binds to it diagonally - binding crosses alpha 1 & 2 domains/ top part of PBG and alpha helices on the side of the groove
- ensures contact with MHC1 and peptide to identify if they’re self

CD8+ co-receptor binds to the lower, conserved domains - alpha 3 and beta2microglobulin
- doesn’t interfere with TCR binding
- stabilises TCR interactions

20
Q

list different mechanisms pathogens use to subvert presentation of peptides by MHC-I

A

inhibiting MHC-1 transcription, prevent MHC from being made

blocks peptide transport to ER - peptide can’t be presented

retains MHC in ER or targets MHC-1 for disposal in ER

downregulates MHC-1 from cell surface

21
Q

what are KIR receptors? - function?

A

killer Ig-like receptors - present on NK cells

recognises absence/ downregulation of MHC 1 expression

22
Q

how do KIRs work? - missing self mechanism

A

NK cell KIRs recognise the absence/ downregulation of MHC 1 expression

KIR binds to MHC 1 molecules on cell surface - if the cell is healthy and expresses MHC1 = KIR sends an inhibitory signal, inhibits NK cell form releasing lytic granules

if KIR doesn’t detect target MHC1 - no KIR inhibitory signal, NK cell releases lytic granules

23
Q

how does KIR bind to MHC molecules?

A

binds to one side of the MHC1 peptide binding groove, sees some of the peptide - has slight specificity but not as much as TCRs

lesser degree of specificity means KIR can recognise groups of MHC 1 alleles/ variants and not just one specific peptide-MHC complex

24
Q

describe the polymorphism of KIRs

A

multiple variants of KIRs on one NK cell surface can be expressed

different KIRs recognise different MHC class 1 variants - KIR and MHC are both polymorphic, and KIR has a more general specificity

25
Q

what are natural cytotoxicity receptors?

A

activating receptors - provide activating signals to NK cells following attachment of certain ligands

different ligands bind to different activating receptors

26
Q

what are the NK natural cytotoxicity receptor ligands?

A

NKp46, Nkp44, NKp30

others are unknown

27
Q

describe the NK natural cytotoxicity receptor ligands

A

NKp46 - binds viral haemagglutinin, triggers activation of NK cells

NKp44 - binds a ligand expressed on tumour cells and upregulated by viral infection

NKp30 - protein produced under stress conditions - e.g. by tumour cells = binds to activating receptor on NK cells, triggers activation

28
Q

what decides NK cell cytotoxic activity?

A

the balance of inhibitory signals from KIR receptors and activating signals from natural cytotoxic receptors

determines level of overall activation - whether NK kills target cell

29
Q

what happens if a KIR recognises MHC1 but natural cytotoxicity receptors don’t recognise one of their ligands?

A

inhibitory signal given to NK cell from KIR, no activating signal = overall inhibition

no release of lytic granules

30
Q

what happens if a KIR recognises MHC1 and natural cytotoxicity receptors recognise one of their ligands?

A

inhibitory signal from recognising MHC1

activating signal from recognising a ligand - NKp46/44/30

depends on which type of signal outweighs the other - i.e. if activating signals outweigh inhibitory KIR signals = NK cell activity is directed towards lysis

31
Q

why do NK cells kill tumour cells?

A

tumour cells can escape the adaptive immune system/ CD8+ T cells by downregulating MHC1 expression

NK cells can detect MHC1 downregulation - lose inhibitory signal provided by KIR receptors, further detection of potential stress-proteins produced by tumour cells (NKp30)

more activating signals than inhibitory - NK cell kills target

32
Q

what is antibody-dependent cell-mediated cytotoxicity/ ADCC?

A

cell-mediated immune defence where an effector cell of the immune system (e.g. NK cell) kills a target cell

33
Q

mechanism for ADCC?

A

new viral protein from an infected cell starts budding out - proteins become visible on cell surface

pre-existing antibody to virus bind to viral antigens on target cell = form a complex, Fc region of antibody sticks out

NK cell activating receptors bind to Fc region of antibodies - strong activating signal to NK cell = kills target via lysis

34
Q

what is contained within the cytotoxic/lytic granules NK cells and CD8+ T cells release? - functions?

A

perforin, granzymes, granulysin - targeted release of granules into target cell specifically

perforin - punches holes in target cell membrane, allows granule contents to enter cytoplasm

granzymes - serine proteases, trigger apoptosis

granulysin - induces apoptosis once it gets into target cell cytoplasm

35
Q

function of granulysin?

A

trigger apoptosis once in target cell cytoplasm

36
Q

function of granzymes?

A

trigger apoptosis

37
Q

function of perforin?

A

punches holes into target cell membrane - ensures granule release into target cell cytoplasm

38
Q

why aren’t cytotoxic NK/CD8+ T cell granules released into extracellular space?

A

would cause bystander damage of other healthy cells

39
Q

describe the targeted release of cytotoxic granules by CD8+ T cells into target cell via a immunological synapse

A

CD8+ T cell comes into contact with target cell through non-specific adhesion

TCR and co-receptors cluster at site of cell-cell contact - more specific
- TCR triggers cytoskeleton rearrangements within itself to deliver granules directly where the TCR is in contact with the target cell
- granules released at point of contact

targeted granule release through formation of immunological synapse between TCR and target cell at point of contact

40
Q

how do CD8+ T cell trigger apoptosis through Fas-FasL interactions

A

FasL on T cells multimerises Fas protein on surface of target cell

Fas complex death domains bind to FADD death domains on target cell - triggers apoptotic signalling mechanism = cell death

41
Q

compare cytotoxic granule release with Fas-FasL interactions to cause target cell death

A

Fas-FasL interaction is slower - thought of to dispose of unwanted lymphocytes

cytotoxic granules - faster, direct killing of target cell through release of enzymes (perforins, granzymes, granulysin)

42
Q

compare NK cells with CD8+ T cells

A

NK cells:
- don’t use a co-receptor for MHC 1
- express multiple receptors - activating and inhibitory recs and their variants, KIRs have broader specificity for MHC1 and its variants
- presence of appropriate MHC 1 ligand results in inhibition of killing, absence of MHC = activates killing
- ready to act on encountering targets in the periphery
- can detect tumour/ virally infected cells that downregulate MHC 1

CD8+ T cells:
- use CD8 co-receptor for MHC 1
- each CD8+ T cell expresses one unique TCR with high specificity for peptide-MHC binding with CD8 co-receptor
- presence of foreign MHC1/ peptide activates killing, presence of self MHC1/peptide means no killing
- T cell response requires initial activation of naïve T cells in lymph nodes, differentiation, cytokine signals and proliferation

43
Q

similarities between CD8+ T cells and NK cells

A

destroy infected/ malignant cells

used shared cytotoxicity mechanisms - immunological synapse and targeted release of cytotoxic granules

Microbiology & Immunity (37 decks)

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