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Clinical Immunology > Lecture 5 - NK cells > Flashcards

Lecture 5 - NK cells Flashcards

1
Q

Lineage

A
  • The “Common Lymphoid Progenitor” in the bone marrow gives rise to all lymphocytes (including T, B and NK cells)
  • NK cells discovered in 1970s – large lymphocyte with granular cytoplasm
  • NK cells lack antigen specific receptors (T cell receptors on T cells, B cell receptors on B cells)
  • NK cells express various types of innate receptors (respond to cellular surface ligands)
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2
Q

Innate Lymphoid Cells (ILC)

A

• Lymphocytes derived from common lymphocyte progenitor

  • Expression of transcription factor Id2 repress T and B cell development
  • Absence of T and B cell receptors and co-receptors
  • Express receptor for IL-7

• Migrate to peripheral tissues (dermis, small intestine, Lung)

  • 3 types of ILC
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3
Q

ILC 1

A

simulated by IL-12 & IL-18 from Macrophages and DC. Produce INFɣ for defence against viruses and intracellular pathogens. NK cells are a subset
of ICL1, however ILC1 requires IL-7 for growth and development and NK require IL-15 (NK cells in blood and periphery).

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4
Q

ILC 2

A

stimulated by Thymic stromal lymphopoietin (TSLP) and IL-33. Produce IL-4, IL-5 and IL-13. Protect against parasites.

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5
Q

ILC 3

A

stimulated by IL-1β, IL-23. Produce IL-17 and IL-22. Defence against bacteria and fungi.

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6
Q

Natural killer (NK) cells

A
  • Lymphoid cell (subtype of ILC1)
  • Kill infected, stressed or tumour cells
  • Release toxic granules (similar to CTL)
  • They are ready for action once they leave the bone marrow (no further differentiation required)
  • 5 – 15% of mononuclear cells in Blood
  • Express germline DNA encoded receptors
  • (T and B cell receptors are derived from somatic recombination)
  • In humans - identified by expressing CD16 (binds Fc region of IgG) and CD56 (adhesion molecule), as well as the absence of CD3
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7
Q

CD3-, CD56+

A
  • Cytotoxic NK cells (blood) = CD3-, CD56lo, CD16+

* Immunomodulatory NK cells (LN) = CD3- , CD56hi, CD16-

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8
Q

Role of NK cells

A

•Part of the innate immune system (unlike T and B lymphocytes)

•NK cells eliminate both virally infected, stressed
cells and tumours

  • Direct contact - cytotoxicity by release of toxic
    granules (perforin and granzymes), apoptosis
  • Indirectly - produce IFN-ɣ and TNF
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9
Q

Indirect protection (NK cells)

A

• Activity of NK cells increased 20-100 fold by IFN-α, IFN-β or IL-12 produced by macrophages and DC
- Response to many pathogens but especially virus
infections

• NK cells also produce large amounts of INFɣ and TNF
- Activates macrophages, stimulates DC, induces CD4 to TH1 (Cytotoxic T cells and IgG)

• Serve to contain virus infection before Cytotoxic T cells or neutralizing antibodies of adaptive immune system starts

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10
Q

Direct contact (NK cells)

A

• NK cells eliminate both virally infected and cancer cells by direct contact

  1. NK cells recognize reduced MHC class I molecules via activating and inhibitory receptors
  2. Antibody Dependent Cell Mediated Cytotoxicity (ADCC) (NK cells can attach to antibodies (via Fc receptor on surface of cells)
  • Direct cytotoxicity by release of perforin and granzymes (Similar to CD8 cytotoxic T cells)
  • NK cells also can induce apoptosis via Fas ligand or tumour necrosis factor related apoptosis inducing ligand (TRAIL)
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11
Q

Apoptosis

A
  • Damaged, old or stressed cells need to be removed.
  • The mechanism for this is called apoptosis
  • Cells often express receptors (Fas and other death receptors) when stressed that once bound to the ligand initiate apoptosis
  • NK cells have Fas ligand (CD95L) on their surface, that binds to Fas (CD95) on target cell
  • Tumour necrosis factor related apoptosis inducing ligand (TRAIL) binding to death receptors (DR4 & DR5) on target cell
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12
Q

Activating and Inhibitory Receptors

A
  • NK cells can distinguish health cells from infected and stressed cells by surface molecules
  • By activating and inhibitory receptors on NK cell surface
  • NK cell activity is regulated by a balance between signals from these receptors
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13
Q

Activating receptors

A
  • Stimulate protein kinases that phosphorylate down stream signalling substrates
  • Activating receptors usually bind molecules that are expressed as a result of infection or malignancy (stress induced self)
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14
Q

Inhibitory receptors

A
  • Stimulate phosphatases that counter the kinases
  • When inhibitory receptors engaged the signal stops the activating signal
  • Inhibitory receptors usually bind surface molecules that have high expressing and loss of these molecules indicate dysfunction (missing self)
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15
Q

Receptors on NK cells

A
  • Balance of activating and inhibitory signals determines outcome of target cell
  • Many different receptors on NK cells respond to a variety of ligands on target cell surfaces (Many receptors, particularly inhibitory receptors, bind MHC class 1)
  • Some of these receptors are very polymorphic and so different individuals will respond differently (similar to the MHC)
  • Different NK cells express receptors to a larger or less degree than other NK cells within an individual (So NK cell populations, within a person, respond differently)
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16
Q

NK cell receptors

A
  • Killer immunoglobulin-like receptors (KIR)
  • Killer lectin-like receptors (KLR)
  • NKG2 and CD94
17
Q

Killer immunoglobulin-like receptors (KIR)

A
  • Major receptors in humans
  • Polymorphic
  • Activating and inhibitory
18
Q

Killer lectin-like receptors (KLR)

A
  • Ly49 receptors in mice
  • Polymorphic
  • Activation and inhibitory
19
Q

NKG2 and CD94

A
  • Both lectin-like receptors
  • Form heterodimer together
  • Interact with HLA-E in humans and Qa1 in mice
  • HLA-E is not polymorphic but binds fragments of other HLA class 1 – detects reduced HLA class 1 (NKG2A, C, E and F)
  • NKG2D activating receptor binds MIC-A, MIC-B and RAET1 family which are induced by stress
20
Q

Inhibitory and Activating Cytoplasmic tails

A
  • Immunoreceptor tyrosine-based inhibition motif (ITIM)

* Immunoreceptor tyrosine-based activation motif (ITAM)

21
Q

Immunoreceptor tyrosine-based inhibition motif (ITIM)

A
  • When ligands bind (extracellular) the tyrosine in the ITIM becomes phosphorylated
  • Binds intracellular tyrosine phosphatases (SHP-1 and SHP-2)
  • Phosphatases (SHP-1 and SHP-2) become localised at cell membrane
  • These inhibit signalling by other receptors by removing phosphates from tyrosine residues of other signalling molecules
  • Long tails for KIR
22
Q

Immunoreceptor tyrosine-based activation motif (ITAM)

A
  • Cytoplasmic tail associated with signalling protein called DAP12 (containing ITAM)
  • When ligation occurs ITAM becomes phosphorylated and activates tyrosine kinases (Syk or ZAP-70)
  • Further signalling lead to release of toxic granules
23
Q

Killer Immunoglobulin-like Receptors (KIR)

A
  • Major receptors on NK cells in humans
  • Members of immunoglobulin superfamily
  • 17 genes or pseudogenes
  • Encoded on Chromosome 19
  • Highly polymorphic
  • Number and type of KIR genes present
  • Allelic variation within each KIR gene
24
Q

KIR structure & nomenclature

A

• Extracellular Ig domains (D)

  • 2D (binds HLA-C)
  • 3D (binds HLA-A & B)

• Cytoplasmic tail

  • Long (L) - inhibitory
  • Short (S) - activating

• For example

  • KIR3DL1
  • KIR2DS2
25
Q

KIR genotypes

A

• NK cell action depends on balance of activating and inhibitory signals

  • Activating KIR provide responsiveness
  • Inhibitory KIR provide self-tolerance
  • KIR bind to HLA-A, B and C (classical MHC class 1)
  • KIRs are members of the immunoglobulin superfamily which are located on chromosome 19q13.4 in the leukocyte receptor complex (LRC)
26
Q

KIR genes

A
  • KIR contains 17 genes
  • P in the name indicates a psuedogene
  • Different individuals will have different sets of KIR genes forming “haplotypes”
  • “A” haplotype is absence of any of the B haplotypes genes
  • “B” is has more activating KIR than A
27
Q

NK cells and Cancer

A
  • NK cells kill many types of tumour cells
  • Also respond to the absence of class I MHC molecules because the recognition of class I MHC molecules delivers inhibitory signals to NK cells.
  • Some tumours lose expression of class I MHC molecules, perhaps as a result of selection against class I MHC–expressing cells by CTLs.
28
Q

NK cells and Cancer (loss of MHC class I)

A 
• Loss of class I MHC molecules makes the tumours particularly good targets for
NK cells.

• Some tumours also express MIC-A, MIC-B, and ULB, which are ligands for the NKG2D activating receptor on NK cells.

29
Q

NK cells targeted to tumour cells

A

• In addition, NK cells can be targeted to IgG antibody–coated tumour cells by Fc receptors (FcγRIIIor CD16).

• The tumouricidal capacity of NK cells is increased by
cytokines, including type1 interferon (IFN-αβ), IL-15, and IL-12, and the anti-tumour effects of these cytokines are partly attributable to stimulation of NK cell activity.

30
Q

How do Innate Lymphoid cells (ILC) differ from T and B

lymphocytes?

A
  • Expression of transcription factor Id2 repress T and B cell development
  • Absence of T and B cell receptors and co-receptors
  • Express receptor for IL-7
31
Q

What role do NK cells play in the immune system – what do they protect against?

A
  • NK cells respond to cellular surface ligands
  • Kill infected, stressed or tumour cells
  • Release toxic granules (similar to CTL)
  • Express germline DNA encoded receptors
32
Q

How would identify an NK cell by flow-cytometry?

A

Labelling lymphocytes with fluorescent antibodies specific for CD16, CD56 and CD3, followed by flow cytometry analysis, enables the identification of NK cells and distinguishes them from NK-T cells

33
Q

Describe the indirect mechanism by which NK cells destroy target cells

A
  • produce IFN-ɣ and TNF

- this activates macrophages, stimulates DC, induces CD4 to TH1 (Cytotoxic T cells and IgG)

34
Q

What is the “missing self” hypothesis?

A

According to the ‘missing self’ hypothesis, one function of NK cells is to recognize and eliminate cells that fail to express self major histocompatibility complex (MHC) class I molecules

35
Q

How do activating and inhibitory receptors work in identifying target cells to kill?

A
  • Activating receptors usually bind molecules that are expressed as a result of infection or malignancy (stress induced self)
  • Inhibitory receptors usually bind surface molecules that have high expressing and loss of these molecules indicate dysfunction (missing self)
36
Q

List and describe the types of receptors used by NK cells.

A
  • Killer immunoglobulin-like receptors (KIR)
  • Killer lectin-like receptors (KLR)
  • NKG2 and CD94
37
Q

What does KIR stand for?

A

Killer immunoglobulin-like receptors

38
Q

How would you describe KIR2DS1 what haplotype would a person have this KIR be?

A

2D - binds HLA-C
S - Short (activation)

this is a B haplotype and is more activating

39
Q

Describe the direct contact mechanisms by which NK cells destroy target cells

A
  1. NK cells recognize reduced MHC class I molecules via activating and inhibitory receptors
  2. Antibody Dependent Cell Mediated Cytotoxicity (ADCC)

• NK cells can attach to antibodies (via Fc receptor) on surface of cells

Clinical Immunology (15 decks)

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