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Infection and Immunity > NK cells and Gamma/Delta T cells > Flashcards

NK cells and Gamma/Delta T cells Flashcards

1
Q

What are NK cells?

A

A subset of innate lymphoid cells

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2
Q

What determines the phenotypic differences between ILC subsets?

A

Transcription factors
e.g. T-bet, GATA3 and RORgt

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3
Q

What are the type of gd T cells?

A

Vd1 - skin, lung, gut
Vd2 - blood, lymph node, spleen
Vd3 - blood (rare)

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4
Q

Describe NK cells

A

Large granular lymphocytes that are not T or B cells
Do not express TCR or BCR
Do not express cell surface marker CD56
CD3- CD56+

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5
Q

What do NK cells do?

A

Cytokine secretion
Cytotoxicity causing lysis of target cell

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6
Q

What defines NK cell subsets?

A

CD56 expression level
10% of NK cells are CD56bright, 90% are CD56dim

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7
Q

Describe CD56bright NK cells

A

Predominantly found in secondary lymphoid organs
Greater cytokine production
Low level of perforin/granzymes

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8
Q

Describe CD56dim NK cells

A

Low CD56 expression
Predominantly found in blood
Highly cytotoxic
High level of perforin/granzymes

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9
Q

What are the cytokines released by NK cells?

A

IFN-g
TNF-a

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10
Q

What does IFN-g released by NK cells do?

A

Activation, growth and differentiation of T, B, NK cells and macrophages
Promotes Th1 differentiation
Enhances MHC expression on APC

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11
Q

What does TNF-a released by NK cells do?

A

Inflammatory mediator
Regulates growth and differentiation of a wide variety of cells
Selectively cytotoxic for many transformed cells

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12
Q

What do NK cells release to kill target cells?

A

Lytic granules containing proteins that act on the target cell

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13
Q

What proteins do lytic granules of NK cells contain?

A

Perforin
Granzymes
Granulysin

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14
Q

What does perforin do?

A

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

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15
Q

What are granzymes and what do they do?

A

Serine proteases
Activate apoptosis once in the cytoplasm of the target cell

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16
Q

What does granulysin do?

A

Has antimicrobial actions and can induce apoptosis

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17
Q

Describe the role of NK cells in cancer

A

Medium and high cytolytic function of NK cells = reduced cancer risk (because NK cells are in abundance and can fight cancer cells)
Low cytolytic function = increased cancer risk
LAK cell therapy can be used for individuals with low cytolytic function

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18
Q

How do LAK cells work?

A

Lymphokine-activated killer cells
In the presence of IL-2 they are stimulated to kill tumour cells
They have many receptors/adhesion molecule on their surface for IL-2 so they are cultured to increase cell division into the cytotoxic line of cells and become activated to kill cancer cells

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19
Q

Describe the role of NK cells in infection

A

Low NK activity = increased risk of herpesvirus infections

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20
Q

How are NK cells activated in viral infection?

A

Virus infected cells release IFN-a and IFN-b
This induces resistance to viral replication in all cells
Increase MHC-I expression and antigen presentation in all cells
Activate NK cells to kill virus infected cells

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21
Q

How do NK cells make the decision to kill?

A

Fc receptor recognition of Ab/Ag complexes
Balance of activating/inhibitory receptors - detection of missing self and detection of induced self

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22
Q

What is missing self?

A

When there is an absence or altered expression of MHC-I molecules
Inhibitory receptors on NK cells cannot bind to MHC-I which leads to cell lysis of the target cell

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23
Q

What is induced self?

A

When target cells express activating ligands that bind to activating receptors and result in NK cell killing
However if MHC-I present and binds to inhibitory receptor then there is balance of activating/inhibitory receptors, resulting in no killing

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24
Q

Describe antibody-dependent cell-mediated cytotoxicity (ADCC)

A

Ab bind Ags on surface of target cells
CD16 (FcgRIII) on NK cells allows them to bind to Ab-coated targets
Cross-linking of Fc receptors signals the NK cell to kill the target cell
e.g. Rituximab and CD20 in Burkitt’s lymphoma

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25
Q

Describe how Rituximab causes killing of Burkitt cells

A

Rituximab is a monoclonal antibody
Binds to CD20 on Burkitt cells
CD16 on NK cells will bind to Rituximab and cause cross-linking of the Fc receptors
Burkitt cells are killed

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26
Q

How to inhibitory receptors signal?

A

Through ITIMs

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27
Q

How do activating receptors signal?

A

Through ITAMs

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28
Q

What receptors regulate NK cell function?

A

Killer Ig-like receptors (KIR)
Leukocyte Ig-like receptors (LILR)
Both are encoded in the leukocyte receptor complex (LRC) on chromosome 19

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29
Q

Describe KIR

A

Innate immune receptors
Regulate the activity of NK cells
Polymorphic
Individual KIR genes vary in their presence between individuals

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30
Q

Describe LILR

A

Innate immune receptors
Regulate functions of NK cells and APCs

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31
Q

Describe how KIRs function

A

When KIR recognise MHC-I they inhibit NK cells from releasing lytic granules
Some viruses downregulate MHC-I to evade cytotoxic T cells
If a target cell does not express MHC-I then there is no KIR inhibition
Lytic granules will then be released to lyse the target cell
Known as missing self

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32
Q

What do inhibitory KIR bind to?

A

The same face of MHC-I as the TCR

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33
Q

What do the KIRs recognise?

A

Subsets of MHC-I alleles

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34
Q

What do different MHC-I/KIR combinations show?

A

Disease associations
e.g. in HIV infection

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35
Q

What happens in the interaction of an NK cell with a healthy autologous cell?

A

No killing of healthy autologous cell

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36
Q

What happens in the interaction of an NK cell with a healthy allogeneic cell of similar HLA-C type?

A

No killing of allogeneic cell of similar HLA-C type

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37
Q

What happens in the interaction of an NK cell with a healthy allogeneic cell of different HLA-C type?

A

Killing of healthy allogeneic cell of different HLA-C type

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38
Q

Why are tumour cells susceptible to NK cells?

A

Tumour cells downgrade the expression of MHC-I
This means inhibitory receptors on NK cells will not bind to the tumour cell
Causes lysis of tumour cell

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39
Q

How are KIR receptors named?

A

Based on number of Ig domains
Whether they have a long or short cytoplasmic tail - inhibitory receptors have long tails, activating receptors have short tails
e.g. KIR3DL1 = 3 Ig domains, long cytoplasmic tail
KIR2DS1 = 2 Ig domains, short cytoplasmic tail

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40
Q

What do NK cells need to become mature?

A

Ligation of inhibitory receptors
This supposes that the inhibitory receptors play 2 opposing roles dependent on the stage of NK maturation - to license the cell and to stop cytotoxicity

41
Q

How do inhibitory and activating receptors exist?

A

As heterodimers

42
Q

What is the name of the inhibitory receptor?

A

CD94/NKG2A, B
KIR2DL
KIR3DL

43
Q

What are the names of activating receptors?

A

CD94/NKG2C
CD94/NKG2E
KIR2DS
KIR3DS

44
Q

What do inhibitory and activating receptors recognise?

A

HLA-E on target cell

45
Q

What is HLA-E?

A

Non-classical MHC-I protein that presents leader peptides from other MHC-I molecules (HLA-A, B, C)

46
Q

What does HLA-E bind to?

A

Lectin-like receptors NKG2A, B and C
NKG2A, B and C form heterodimers with CD94

47
Q

Why do we need HLA-E?

A

Some immune cells can be HLA-E-restricted so HLA-E will present the peptides needed for recognition from other HLA class I allotypes
CD94/NKG2A is specific to HLA-E meaning it will not bind to other HLA class I allotypes

48
Q

What is the structure of HLA-E?

A

a1, 2 and 3 subunits
b2m subunit

49
Q

Describe LILRs

A

Encoded adjacent to KIR in the leukocyte receptor complex (LRC)
They have inhibitory motifs - LILRB (inhibitory)
Short tail and associate with adaptor proteins - LILRA (activatory)
Varying expression profiles
LILRB1 expressed by NK cells - powerful immune inhibitor

50
Q

Describe NKG2D

A

Expressed on NK cells, gd T cells, CD8+ ab T cells and macrophages
Associates with DAP10 for signalling
Binds to MHC-I-like proteins, MICA, MICB, ULBPs
Activating

51
Q

What happens when NKG2D recognises MICA, MIC or ULBPs?

A

Release of perforin
Release of IFN-g, TNF-a and GM-CSF

52
Q

What inhibitory receptors recognise missing self?

A

KIR recognise classical MHC
LILR recognise classical and non-classical MHC
NKG2A, B and C recognise non-classical MHC

53
Q

What activating receptors recognise induced self?

A

NKG2D recognise MICA, MICB and ULBPs

54
Q

What are the natural cytotoxicity receptors?

A

NCR1, NCR2 and NCR3

55
Q

What do NCRs do?

A

Provide activating signals to NK cells

56
Q

What are the ligands for NCR1?

A

Viral hemagglutinin

57
Q

What does NCR2 bind?

A

A ligand expressed on tumour cells and upregulated by viral (HIV) infection

58
Q

What is the ligand for NCR3 (NKp30)?

A

BAT3 - a stress induced protein

59
Q

What does target cell death or survival depend on?

A

Balance of activating and inhibitory signals
e.g. if 3 activating ligands bind activating but only 1 MHC binds to inhibitory receptor then target cell is lysed because more activation than inhibition

60
Q

How does cytomegalovirus (CMV) evade immune response?

A

Produces UL16 which binds NKG2D ligands, retaining them in the cytoplasm
This prevents recognition b NK cells and co-recognition of CD8 T cells

61
Q

How do tumours avoid immune response?

A

They produce soluble MIC as a decoy so that the CTLs do not bind to the membrane-bound MIC and cause lysis

62
Q

Describe the role of HLA-G in immune invasion

A

Normally only expressed by trophoblast during pregnancy but is expressed by many tumours and can be upregulated in HIV infection
HLA-G is the highest affinity ligand for LILRB1
LILRB1 is expressed on B cells, NK cells, T cells and APCs and can inhibit the functions of each

63
Q

What are some other innate lymphocytes?

A

B1 cells
Epithelial gd cells
NK T cells

64
Q

Describe B1 cells

A

Make natural Ab - protect against infection with Strep pneumoniae
Ligands no MHC associated
Cannot be boosted

65
Q

Describe epithelial gd cells

A

Produce cytokines rapidly
Ligands are MHC class IB associated
Cannot be boosted

66
Q

Describe NK T cells

A

Produce cytokines rapidly
Ligands are lipids bound to CD1d
Cannot be boosted

67
Q

What is the difference between NK T cells and CD8/CD4 T cells?

A

NK T cells express a biased T cell receptor repertoire
Most NK T cells use a particular TCR alpha chain rearrangement (Va24JaQ) in humans

68
Q

What receptors do NK T cells express?

A

Some inhibitory and activation receptors - relevant in bacterial and viral infection

69
Q

What do NK T cells do?

A

Kill tumour cells in vitro
Produce cytokines

70
Q

What does the NK T cell TCR recognise?

A

Glycolipids in the context of CD1d (MHC I-like molecule)
e.g. alpha-galactoceramide

71
Q

What is DC vaccination?

A

a-galactoceramide molecules are loaded onto DCs and this boosts the NK T cell population
It is used to kill tumour cells

72
Q

Describe CD1

A

Encoded outside MHC
Specialised binding groove presents glycolipids or phospholipids
Many lipids and glycolipids differ between microbes and mammals
Recognised by specialised subsets of TCR - Va24/Vb11

73
Q

What are gamma delta T cells?

A

Unconventional T cells
Mechanism of selection largely unknown
Generally enriched in mucosal and epithelial tissues
MHC independent
Activated by TCR and NK-receptor (NKG2D)

74
Q

What are the functions of gd T cells?

A

Lysis of infected or stressed cells
Cytokine and chemokine production
B cell help and IgE production
Priming of ab T cells via antigen presentation
DC maturation
Regulation of stromal cell function via growth factor production

75
Q

How was the gd TCR discovered?

A

Delta gene found by chance located within the alpha locus
Then gamma gene was discovered when trying to look for corresponding chain

76
Q

Describe the loci of the gamma and delta genes

A

Limited V segments at both loci
Delta has numerous D gene segments

77
Q

How does the gd TCR get its diversity?

A

Junctional diversity leads to potentially many CDR3 sequences

78
Q

What percentage of T cells are gd?

A

Between 1-10% of peripheral blood T cells

79
Q

What is the TCR responsible for according to animal models?

A

Localisation of the cell to tissues
Murine models - Vg3 localise to intestinal epidermis, Vg5 localise to epithelium
Humans - Vg9Vd2 in peripheral blood, Vd1 in epithelial tissue and resident in liver
May involve butyrophilin-like molecules (Btnl)

80
Q

What molecule is expressed in intestinal epithelial cells of mice?

A

Btnl1 or Btnl6

81
Q

What do Btnl1/Btnl6 do?

A

Activate and home intraepithelial cells for Vg7 T cells to intestinal epithelial cells

82
Q

What molecule is expressed in thymocytes of mice?

A

Skint1

83
Q

What does Skint1 do?

A

Induces maturation of Vg5 T cells in the mouse thymus

84
Q

What doe intraepithelial cells for Vg4 in humans bind to?

A

BTNL3/BTNL8 expressed in intestinal epithelial cells

85
Q

How do Vg9Vd2 T cells become activated in humans?

A

Bind butyrophilin itself which presents phosphoantigens
Particular motif binds the phosphoantigens, changing the external conformation
The Vg9Vd2 T cell can then recognise this conformation and become activated

86
Q

What percentage of gd T cells are Vd1?

A

10-30% of gd T cells in the blood

87
Q

Describe Vd1 T cells

A

More highly represented in tissue
Use TCR and NK receptors to identify tumour targets
Recognise CD1d/lipid complexes and NKG2D ligands
MHC recognition (allogeneic)
Role in homeostasis and stress surveillance

88
Q

What percentage of normal PBLs are Vd2?

A

4% but can expand rapidly to 60%+ in infections

89
Q

What do Vd2 T cells recognise?

A

Small phosphoantigens
e.g. isopentenyl pyrophosphate (IPP) and E-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMBPP) presented by butyrophilin3A1
Can also recognise NKG2D ligands

90
Q

Describe butyrophilin

A

Part of the B7 receptor family-like proteins
2 extracellular Ig-like domains
Does not appear to present pAg on the usual, MHC-like way

91
Q

What are the types of butyrophilin?

A

BTN3A1, A2 and A3

92
Q

What is BTN3A1 essential for?

A

pAg recognition

93
Q

What region of BTN3A1 binds pAg?

A

Intracellular region 30.2

94
Q

What does binding of pAg to BTN3A1 do?

A

Changes the conformation of the extracellular portion of BTN3A1
Allows it to be recognised by Vg9Vd2 cells

95
Q

What are effector functions of gd T cells?

A

Cytokine production - Th1-like prod IFN-g and TNF-a, Th17-like prod IL-17
Cytotoxicity against infected or transformed cells
Degranulate like NK cells, perforin, serine esterases, granulysin
Thought to be a rapid response in immunosurveillance

96
Q

What drugs are used in gd T cell therapy?

A

Aminobisphosphonates
Pamidronate
Alendronate
Zoledronic acid

97
Q

What does gd T cell therapy do?

A

Blocks mevalonate pathway and causes accumulation of IPP
IPP binds 30.2 region of BTN3A1 and causes activation of Vg9Vd2 T cells

98
Q

What is BCG?

A

Bacille Calmetter-Guerin
A vaccine form of Mycobacterium bovis used to prevent tuberculosis and other mycobacterial infections

99
Q

What is the significance of BCG in relation to gd T cells?

A

BCG activates Vg9Vd2 cells and these cells are better at killing tumours than zoledronic acid

Infection and Immunity (33 decks)

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