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Cytotoxic T cells and NK Cells Flashcards

1
Q

What do CD8+ T cells recognise?

A

Peptides presenter by MHC class I

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2
Q

What do MHC class I sample?

A

Intracellular antigen

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3
Q

Why are CD8+ T cells important?

A

All viruses and some bacteria live in the cytoplasm of cells (CD4 will survey and protect extracellular pathogen) Once inside a cell they cannot be reached by antibodies To remove these pathogens, the infected cells have to be eliminated Need to be powerful but precise

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4
Q

What activates the dendritic cell?

A

The acquisition of virus

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5
Q

At the lymph node [priming CD8+ T cells]

A

Activation of naive CD8+ T cells [recognition phase] MHC class I recognises the T cell (signal 1) Brings signal 2 with cd28 costimulation Lead to signal 3/ cytokine response Leave the lymph node and go to tissue for an effector function Expansion of antigen specific clones (proliferation/differentiation)

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6
Q

At tissue cells (priming CD8+ T cells)

A

Killing of infected cells First antigen recognition event: priming (lymph node) Second, third, fourth of antigen recognition event: effector function (killing)

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7
Q

What does naive CD8+ cytotoxic T cell recognise?

A

Alpha-beta chain of TCR

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8
Q

What does TCR need to have?

A

CD3 domain to transmit signal inside the cell

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9
Q

Signal 1

A

MHC peptide + antigen recognise TCR + CD3

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10
Q

What is the stimulus transduced by?

A

CD8 recognising B3 chain of MHC I + peptide

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11
Q

What does tyrosine kinase do?

A

Phosphorylate CD3 to TCR which sets a response

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12
Q

What happens if CD28 is missing?

A

T cells become anergic

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13
Q

What does CD28 stabilise?

A

Transcription factors on IL-2 site

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14
Q

What does the production of IL-2 cause?

A

CD8 T cells to expand and proliferate

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15
Q

Where is CD40 present and why is it crucial?

A

Virally infected dendritic cell and is important for full activation

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16
Q

What are naive CD8+ cytotoxic T cell activated by?

A

Fully activated dendritic cell in the lymph nodes

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17
Q

What does the fully activated/mature dendritic cells express?

A

Fully complement of co-stimulators molecules e.g. B7 and CD40

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18
Q

How does CD4+ T cell help activate CD8 T cell?

A

Licence dendritic cell for stimulation of CD8+ T cells Recognise dendritic cell and make cytokines to activate CD8 T cell Interact with CD40 ligand Activation of CD80/86 will activate APC

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19
Q

High antigenic load

A

Sufficient for CD8 to recognise the DC

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20
Q

Low antigenic load

A

APC is not sufficiently activated to prime CD8 T cell

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21
Q

What happens once CD8+ cytotoxic T cells are activated by dendritic cells?

A

Armed CD8+ cytotoxic T cells recognise and kill virally/bacterially infected/tumour cells in the tissue

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22
Q

What cells have MHC class I molecules presenting virus peptides?

A

Only infected cells

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23
Q

Where does killing always happen?

A

In the tissue

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24
Q

How can cell death occur?

A

Apoptosis

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25
Apoptosis
Quiet and controlled
26
Necrosis
Uncontrolled
27
What is Apoptosis
Programmed cell death
28
Apoptosis
Kills the host cell- this host cell cannot continue to make pathogens Cell membrane remains intact - no release of pathogens or toxic cellular components Apoptosis cells removed by phagocytes without induction of co-stimulators molecules Destroys any cytosolic pathogens due to enzymes involved
29
Necrosis
Caused by chemical or physical injury Uncontrolled Cell pops Pathogens would be released, propagating infection Toxic compound would be released
30
What are the characterises of apoptosis ?
Nuclear blebbing Alteration in cell morphology Cell membrane remain intact Shedding of small membrane vesicles DNA is fragmented by controlled digestion by nuclease enzymes Apoptotic bodies removed by phagocytic cells
31
What does armed cytotoxic T cells have?
Lytic granules (modified lysosomes)
32
What are the lytic granules?
Perforin Granzymes Granulysin SerglycinA
33
Perforin
Modifies the target cell to facilitate entry of granzymes [complement to C9]
34
Granzymes
Proteases start chopping up proteins In the target cell
35
What are two examples of Granzymes
Granzymes A: kill by chopping cell nuclear comments and cytoplasmic components Granzymes B: mitochondrial membrane become hyper-polarised and leaky - mitochondria pop
36
Granulysin
Antimicrobial activity
37
SerglycinA
scaffold protein that aids in delivery of perforin and granzymes
38
How do cytotoxic T cell kill?
Granzymes and perforin
39
What does granzymes and perforin release?
Granules from cytotoxic T cells
40
What are 2 mechanisms in which perforin facilitate entry of granzymes into the cell
Perforin forms a ring structure on the outside of target cells and puncture it and granzymes go in through the perforin ring The perforin and granzymes are endocytosed completely - form endosomes and perforin form a ring structure on endosomes and granzymes goes in on endosomes
41
What effect does granzymes have?
Upregulate caspase and activate them
42
What do caspases remove?
Inhibitory domain of I-CAD and form functional caspases activated DNASEs ( enzymes that goes in and choose DNA)
43
How are cytotoxic effector molecules released?
Precisely focused manner
44
What do LFA-1 recognise?
I-CAM (intracellular adhesion molecule)
45
What does the interaction of LFA- and I-CAM cause?
Pull cytotoxic T cell close to the target [directed-Hit]
46
What are the characteristics of cytotoxic effector molecules?
Reorganisation of MTOC and Golgi Lytic granule release Cell death by Apoptosis
47
What does the immunological synapse describe?
Contact of a T cell to its target
48
What is the area of contact called of immunological synapse?
Supramolecular adhesion complex (SMAC)
49
Peripheral SMAC
LFA-1: ICAM-1 [larger molecule]
50
central SMAC
TCR:MHC:peptide, CD8
51
1 CD8 can kill up to how many times?
26
52
What is FAS ligand?
Death receptor - recruit death domain which activate caspases through removal of inhibitory domain - removed from caspases that then goes and cleaves DNA- shredding it and making to ready for Apoptosis
53
Caspase
Enzyme that cleaves protein (stands for Cuts at Aspartic acid - ase)
54
CAD
Caspase-Activatable DNAse | Enzyme that cleaves DNA
55
I-CAD
A protein which inhibits CAD
56
What do CD8+ T cells make?
Cytokines: IFN Gamma, TNF alpha and LTalpha
57
What does IFN Gamma do?
Increase MHC class I expression Upregulate antigen processing machinery Increase macrophage recruitment and activation
58
What are NK cells?
Natural killer cells
59
Where is NK cell developed?
Bone marrow, part of lymphoid lineage
60
What does NK cell express?
Low levels of CD8 but not the CD3 complex
61
What is the role of NK cells?
Potent killers in the innate immune system | Kill target cell using similar machinery to CTL (performing, granzymes)
62
What does NK cell not require?
Priming
63
Where is NK cells important?
Early in infection (limit viral replication until CTL response develops)
64
What are NK cells activated by?
``` Cytokines Type I interferons and IL-12 IFN alpha IFN Beta TNF alpha ```
65
What does NK cell respond rapidly to?
Viral infection
66
What are NK cells important against and give examples
``` Intercellular pathogens Herpes viruses Leishmania (protozoan Parasite) Listeria monocytogenes (bacterium) And against tumours ```
67
What does NK cells not tend to eliminate?
Viruses
68
What does NK cells possess?
Both activating and inhibitory receptors
69
What does inhibitory receptors recognise?
Self component of healthy cells - MHC class I
70
What does activating receptors recognise?
Molecules associated with cell stress
71
What is NK cells?
Highly polymorphic | Undergo allelic conversions
72
How does TCR and BCR get their variability?
Chromosomal rearrangement VDJ
73
In the absence of infection
``` Recognition of self and inhibition dominates Inhibitory receptors recognise MHC class I and cause production of phosphatases which remove the phosphorylated region of ITAM ```
74
How do you keep the NK cells quiet?
Predominance of inhibitory receptors
75
In the presence of infection
The balance shifts The inhibitory signal is lost Ligand associated with cell stress increase Inhibitory signal lost because Virus will internalise MHC class I or loss of self-recognition Lose the ability of phosphatases to cleave the activatory regions Activatory signal predominates
76
What are the 2 groups in humans the NK receptors are broken into?
LKC | NKC
77
What are typical stress molecules?
MICA and MICB
78
What is ADCC mediated by?
Cells expressing receptors for the Fc region of antibody molecules FcgRIII/CD16 recognising IgG1/IgG3
79
Where is low affinity for F.C. region of Antibodies found?
Constant region
80
What is role in killing?
Virally infected cells Helminths Tumour cells May be utilised for therapies e.g. Herceptin/trastuzumab
81
What does CD16 recognise and bind to?
FC portion of the antibody such as IgG which has bound to the surface of pathogen infected target cell

Immunology (20 decks)

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