NK cells Flashcards

1
Q

LO

A
  • Explain the basic biology of NK cell biology; identifying key receptors important for NK function
  • Identify the role of NK cells in an immune response and how viruses and cancer attempt to evade them
  • Describe how NK cells may be part of the adaptive immune system and how they interact with adaptive immune cells
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2
Q

NK cell lecture topics

A
  • What are NK cells?
  • Activation of NK cells
  • Recognition of infected/cancer cells
  • Diversity in NK cells
  • CMV and NK cells – evolution and co-evolution
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3
Q

What is the break down of the immune system, tell me the sub-divisions of each and what is included into each.

Where do NK cells fit into this?

A

Innate

  • Humoral- complement, haptoglobin
  • Cellular- granulocytes, NK cells

Adaptive

  • Humoral- antibodies, B cells
  • Cellular- T cells

Linkers

  • Humoral- cytokines, chemokines
  • Cellular- dendritic cells
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4
Q

Draw a graph with titre on the y-axis and time on the x-axis and draw on the lines of:

adaptive immune response

innate immune response

virus titre

A
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5
Q

Tell me about the evolution of NK cells

A
  • NK cells evolved much earlier than other lymphocytes
  • Fundamental role in the immune system
  • First described in 1975
  • Kiessling et al Eur J Imm
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6
Q

What is the innate immune system cell lineage, where do NK cells come into this lineage?

A
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7
Q

What types of cells are NK cells, how do they exist in the blood?

A
  • lymphocytes
  • cytotoxic, small granular cells
  • contains small granules in their cytoplasm which contain proteins such as perforin and proteases known as granzymes
  • monomorphic lineage
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8
Q

What are some of the roles that NK cells have in the body?

A

Anti-viral response

  • Herpes group of viruses (CMV, VZV, HSV, EBV)
  • Bacterial infections?

Emerging role in anti-tumour response

Interface with adaptive immune system

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9
Q

How can NK cells be identified?

A
  • Use flow cytometry to distinguish cell types
  • Flow cytometry is a technique used to detect and measure physical and chemical characteristics of a population of cells or particles and looking at the cell’s markers also
  • NK cells are CD3- / CD56+
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10
Q

Tell me the function of NK cells, what are the main three?

A

NK cells are important in anti-viral activity and can shape the adaptive immune response

1) Primary role is to kill target cells
2) Proliferate to generate more NK cells to kill target cells
3) Recruit other immune cells

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11
Q

In which two ways do cytokines stimulate NK cells following activation

A
  • Cytotoxicity
  • Proliferation
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12
Q

What cytokines are involved in NK cell cytotoxicity?

A

Cytotoxicity = IFN-alpha, IL-2, IL-12 and IL-15

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13
Q

What cytokines are involved in NK cell proliferation?

A

Proliferation = IFN-gamma, IL-12, IL-15, IL-18, and IL-21

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14
Q

How do cytokines work in order to stimulate NK cells following activation?

A

Synergistically

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15
Q

NK cells secrete cytokines following activation,

What cytokines are released, especially in the following circumstances…

  • Th1 cell activation
  • Th2 cell activation
A

IFN-gamma, TNFalpha and GM-CSF – Activation of Th1 cells

IL-4 and IL-10 – Activation of Th2 cells

MIP-1beta

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16
Q

What are the three main ways in which NK cells kill?

What types of interactions are involved in each?

A

Antibody dependent cellular cytotoxicity (ADCC)

  • FcgRIII interaction (receptor on cell surface)

Natural cytotoxicity

  • Receptor-ligand interaction

Apoptosis of infected cell

  • Fas-Fas ligand/TRAIL-DR4
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17
Q

What are the steps to antibody depdendent cellular cytotoxicity of NK cells?

A
  1. Antibodies bind to cell surface
  2. NK cells bind to antibody - mediated by CD16 (FcgRIII)
  3. NK cell secretes perforin – induces lysis of target cell
  4. Target cell death
  5. NK cell secretes cytokines and chemokines which activate other immune cells
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18
Q

How does natural cytotoxicity of NK cells occur?

A

Receptor/Ligand interaction between proteins on NK and target cell surface

Induces activation leading to release of cytotoxic granules (perforin/granzyme)

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19
Q

However, NK cells do not just have an activating interaction, they also have inhibitory receptors. There is a balance between these two receptors.

What are the different inhibitory and activating receptors of the NK cell?

A
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20
Q

Tell me the types of receptors NK cells express and when certain ones may be expressed?

A

T cells and B cells only express one receptor, TCR and BCR respectively

Co-activating ligands are only expressed on stressed or infected cells

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21
Q

How are NK cells activated?

A

Balance between activating and inhibitory receptors

Natural cytotoxicity receptors (these bind multiple ligands)

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22
Q

What are some of the natural cytotoxic receptors that can activate NK cells?

A

Natural cytotoxicity receptors (these bind multiple ligands)

  • NKp30
  • NKp44
  • NKp46 (binds influenza haemagglutinin- only binds to this ligand when infected with influenza virus)
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23
Q

What is the activation of NK cells important for?

A

important in the recognition of some tumour cell lines

24
Q

What do monoclonal antibodies bind to and what does this block?

A

Monoclonal antibodies bind to natural cytotoxicity receptors to block killing of tumours

25
Q

NK activation signal integration from multiple receptors

A
26
Q

Tell me about NKG2D receptors

Where are they expressed?

What are they important for?

What do they recognise?

A

Important in many processes

Expressed on all NK cells

Activating receptor

Recognises stress induced molecules

Important in Cancer (and viral infection)

27
Q

What are some of the ligands that NKG2D receptors bind to, which are important for cancer?

A

NKG2D binds to a variety of ligands, which resemble major histocompatibility complex (MHC) class I proteins

Important in Cancer (and viral infection)

  • MIC-A/MIC-B
  • ULBP
  • RAE
  • Heat Shock Protein-60
28
Q

NKG2D ligands have multiple levels of regulation

A

NKG2D can interact with molecules fundamental in many different cellular processes

Act as immune surveillance for cells that are cancerous / virally infected

29
Q

What interaction is important in hepatocellular carcinoma (HCC)?

A

The NKG2D amd MICA interaction

MICA, a highly glycosylated membrane-anchored cell-surface MHC Class I-related chain, has recently been reported to activate NK cell cytolytic responses in epithelial tumors. Tumor cells may escape from NK lysis by counteracting NK cytotoxicity activating signals with inhibitory ones.

30
Q

What was shown to increase the probability of an individual to develop HCC?

A

Importance of NKG2D and MICA interaction in hepatocellular carcinoma (HCC)

Identified individuals more prone to develop HCC based on MICA mutations

MICA mutation increased sMICA levels

31
Q

Where is NKG2D expressed?

Where is the ligand for this expressed?

What happens when the receptor and ligand bind?

A

NKG2D expressed on NK cell

Ligand for NKG2D (MICA/B) expressed on tumour cells

Engagement of receptor-ligand = activation

Release of perforins and granzyme to kill target cells

32
Q

What are metalloproteinases that cancer cells secrete when escaping?

A

Metalloproteinases cleave proteins, like NKG2D ligands, at the cell surface- this is secreted by cancer cells as a type of escapes mechanism when it mutates

33
Q

Summary

A

NK cells are innate immune cells with the expression profile CD3- / CD56+

NK cells are important in anti-viral activity and can shape the adaptive immune response

NK cell killing: ADCC, natural cytotoxicity, apoptosis

Dynamic process between NK cell and target cell

  • Activating and inhibiting receptors
34
Q

What are NK cells controlled by a balance between?

A

NK cells are controlled by a balance between activating and inhibitory receptors

35
Q

Explain the missing self-model

A

Many cancers or virally infected cells downregulate cell surface ligands for inhibitory receptors

Lack of inhibitory signal skews response towards activation

Called missing cell model as target cell is missing the cell protein that would activate the response

MHC molecules are expressed on all cells in the body except RBC

Hallmark of cancer and other viral infections is a reduction of MHC I at the cell surface

Upregulation of ligands for activator receptors (for induced self-recognition)

36
Q

Explain MHC class I receptors on NK cells: NKG2 family

A
  • Multigene family
  • Activating and inhibitory
  • Ligands are non-polymorphic MHC class I
  • MHC class I are the most polymorphic cells in our body so they can present thousands of peptides to our CD8 T cells
  • HLA are ligands for NK cells

ITIM= immunoreceptor tyrosine based inhibitory motif

37
Q

Tell me about MHC class 1 receptors on NK cells: killer cell Ig-like receptors (KIR)

A
  • Multigene family
  • Activating and inhibitory
  • Ligands are polymorphic MHC I molecules and MHC class I like molecules
  • Inhibitory KIR have a long domain ‘L’
  • Activating KIR have a short domain ‘S’
  • The number shows what domain it is e.g., KIR3DL is domain 3 and it is long ‘L’
  • L is always inhibitors and S is always activating
38
Q

Where is population diversity present of KIRs?

A

Population diversity of KIR is present both at the level of the locus and at the allelic level

Vary between individual’s dependent on inheritance and geographical location

Different frequencies of the KIR molecules you will express on your cells, also varies on location as shown on map

39
Q

MHC class I ligands for NK cell receptors bind to what families of MHC I molecules?

A

Bind to families of MHC I molecules

HLA-B Bw4+ = KIR3DL1

HLA-C C1 group = KIR2DL2, KIR2DL3,
KIR2DS2

HLA-C C2 group = KIR2DL1, KIR2DS1

HLA-E = CD94:NKG2A

HLA are ligands for NK cells. Killer Ig-like receptors (KIRs) are surface inhibitory receptors specific for allelic forms of HLA class I molecules, which are expressed by NK cells and a subset of T lymphocytes

40
Q

NK cells and vaccinia virus: the “missing-self” model

A
41
Q

What is the lysis of vaccinia infected autologous targets determined by?

A

The expression levels of the inhibitory receptor NKG2A

42
Q

What is HLA-E expression down-regulated by?

A

VV infection

43
Q

Removal of a negatvie signal can result in what when talking about lysis of vaccinia infected autologous targets?

A

result in killing

44
Q

Diversity of NK cells genetics and receptor expression

A
45
Q

What combination is important in response to infection and cancer?

A

Combination of KIR and MHC I is important in response to infection and cancer

46
Q

Activating KIR3DA1 and its ligands, HLA-Bw4, delays progression of what?

A

Activating KIR3DS1 and its ligand HLA-Bw4 delays progression of HIV infection to AIDS

47
Q

Tell me the role of NK cells in diseases like Hepatitis C infection

A
48
Q

Consistent KIR protection in HCV infection

A
49
Q

NK cells can respond efficiently to changes in peptide content of MHC class I

A
50
Q

Altered self: a novel model for NK cells

A
51
Q

What is Cytomegalovirus?

A

Herpes virus

Large genome with many “hijacked” proteins

Common human chronic viral infection

Reactivates following immunosuppression e.g., bone marrow transplantation/HIV

52
Q

What do CD8+ T cells have antigen specific receptors for?

Explain this mechanism

A
53
Q

How does CMV avoid the CD8+ T cell response?

A
54
Q

Tell me the ways in which NK cells are involved in adaptive immunity

A

First described in contact hypersensitivity model (chemical model)

MCMV (virus model):

  • long lived
  • rapid proliferation on Ag challenge
  • enhanced effector functions

Cytokine induced memory:

  • Human
  • Useful for immunotherapy
55
Q

NK cells and delayed type hypersensitivity

A
56
Q

What are the ways in which NK Cells control the adaptive immune response?

A

DCs

Macrophages: malaria

CD16: viral infections

T cells

  • Reciprocal activation of dendritic cells
  • Secretion of cytokines to polarise immune response
  • Direct lysis of T cells
57
Q

Summary

A
  • NK cells express many different receptors that allow them to work against many different target cell lines (cancer and viruses)
  • Receptors can be activating or inhibitory
  • There is an evolutionary” tension” between viruses and NK cells
  • Shape the adaptive immune response