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SEM 4: Immunology > Natural Born Killers > Flashcards

Natural Born Killers Flashcards

1
Q

Briefly explain the innate and adaptive immune systems

A

Innate:

  • non-specific (broadly specific)
  • immediate response
  • can act immediate in the periphery

adaptive:
- highly specific
- delayed response
- need to be activated in the lymph node and proliferate

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2
Q

What is the origin of NK cells and cytotoxic T cells?

A
  • Both arise from common lymphoid progenitor cell
  • Both are part of the lymphocyte lineage
  • NK cells are innate and Cytotoxic T (CD8) cells are adaptive.
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3
Q

What is the role of cytotoxic lymphocytes?

A
  • They are needed to destroy cells: that are infected with bacteria or parasites also those that are malignant, tumour cells.
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4
Q

How do cells recognise what is going on within the cell?

A

Done via cell surface receptors - MHC

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5
Q

What is the role of MHC class I?

A
  • MHC class I proteins are found at the cell surface and form a structure that presents antigenic peptides for surveillance by cytotoxic T cells and NKCs.
  • These are then recognised by CD8+ cytotoxic T cells and NKCs.
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6
Q

What is the interaction between MHC-I and cytotoxic T cells?

A
  1. All proteins including normal ones and viral ones are presented on the MHC-I on the cell surface.
  2. This means that most of the time when cytotoxic T cells are scanning, they are actually coming into contact with normal proteins.
  3. However, if a patient has a viral infection, for example, the cytotoxic T cell will come into contact with a foreign peptide.
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7
Q

What is the MHC-I structure?

A
  • 2 polypeptides which are non-covalently bounded.
  • humans have MHC-I coded by multiple genes e.g. HLA-A, B, C.
  • present on every single nucleated cell in the body
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8
Q

Why is there rarely any mutations in MHC-1?

A

Humans have multiple copies of MHC-1 coded by multiple genes mean there is high genetic variability within the genes so lower possibility of mutation arising.

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9
Q

Where are the MHC polymorphism/variation located?

A

Concentrated in the upper part of the structure around the peptide binding groove.

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10
Q

Why is there variability relating to the binding of the antigen/peptide?

A

Different amino acids depending on different genetic coding in the MHC peptide binding groove create pockets where the bound peptide can anchor.

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11
Q

How are the binding pockets created for the peptide to bind?

A

They are created based on the positive and negative charges from different amino acids

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12
Q

What varies so that different peptides can bind to the different MHC complexes?

A

The size, charge and shape of the pockets vary so different peptides can bind.

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13
Q

What is a central role of MHC I and II?

A

The ability of the immune system to distinguish self and non-self antigens.

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14
Q

What is the T cell receptor (TCR) able to recognise?

A

It is able to recognise the MHC protein itself and the antigen presented by the MHC.

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15
Q

How does the TCR bind to the MHC complex and what does this allow?

A

It binds with a diagonal footprint which allows it to cut across both the alpha helices of the MHC with the peptide. This means both the MHC allele and the peptide can be recognised by the T-cell and therefore it can differentiate whether it is a self or foreign protein.

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16
Q

Why is CD8 (cytotoxic T cells) important?

A

It acts a co-receptor for MHC-1 and is required for an effective T cell response.
It strengths the interaction between the TCR and the MHC-1

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17
Q

Describe the binding of TCR and CD8 to MHC-1

A
  • TCR binds to the a1a2 domains at the top of the complex

- CD8 binds to the support domains a3 and b2m at the bottom of the complex

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18
Q

Why does CD8 bind to the bottom of MHC1?

A

Because this is a highly conserved area, so there are no polymorphisms unlike the top of the structure.

19
Q

How is MHCII have a similar co-binding mechanism to MHCI?

A

CD4 has a similar binding mechanism to MHCII

20
Q

How can microbes such as viruses act on the MHC complex?

A
  • Adenovirus: They can subvert MHC upregulation and inhibit MHC-I transcription.
  • HIV: Inhibit MHC-I transcription
  • HSV: Block TAP activity
  • Adenovirus and HCMV: Retain MHC-I in endoplasmic reticulum
  • HCMV: Target MHC-I for disposal from ER
  • HIV: downregulate MHC-I from cell surface
21
Q

What are classical NK cells?

A

Large granular lymphocytes that are not T or B cells.

22
Q

Properties of NK cells

A
  • They do not express T cell receptor (CD3) or B cell receptor
  • Do express the cell surface marker CD56
23
Q

Functions of NK cells

A
  • Cytokine secretion
  • Cytotoxic function
  • Most of the NK cells seen in the blood are the ones specialised for killing
24
Q

When are cytokine secretions seen?

A
  • Seen more during pregnancy around the site of contact with the placenta
25
Q

What is associated with reduced risk of cancer?

A

Studies have shown medium to high cytolytic function is associated with reduced risk of cancer.

26
Q

What is low NK cell activity associated with?

A

Severe disseminating herpes virus infection

27
Q

What are the two types of receptors on NK cells?

A
  • KIR (inhibitory of killing) and LILR (leukocyte Ig like receptor)
  • Also an activator of killing receptor
28
Q

What are killer Ig like receptor (KIR)?

A

KIR is an innate immune receptor that regulates the activity of natural killer cells

29
Q

What are leukocyte Ig like receptor (LILR)?

A

An innate immune receptor which regulates the function of NK cells.

30
Q

What encodes the KIR and LILR?

A

Both of these are encoded by a gene complex (leukocyte receptor complex) on chromosome 19

31
Q

Describe the action of the KIR

A

Acts to stop killing the cell

  1. When the KIR recognises the MHC-I and binds to it, it inhibits the NK cell from releasing lytic granules.
  2. If a target does not express MHC-I then, there is KIR inhibition and therefore lytic granules will be released to lyse the target - this is called the missing self hypothesis.
32
Q

Why is the missing self hypothesis important?

A

It is important because as mentioned before, healthy cells also display MHC-I, therefore you wouldn’t want to kill them.

33
Q

How have viruses adapted to overcome the adaptive immune system?

A

Some viruses or tumour cells down regulate MHC I in order to stop getting recognised by the adaptive immune system, however, this leads to NO inhibition of KIR and therefore lyses.

34
Q

Where does the KIR bind?

A

It binds to the same face of the MHC-I as the T cell receptor. This means it is able to recognise subsets of MHC-I alleles.

35
Q

How do the KIR genes vary in presence between individuals?

A

Polymorphic and individual KIR genes vary in presence between indivduals

36
Q

Waht is the correlation between MHC-I/KIR and diseases?

A

Different MHC-I/KIR combination are associated with certain diseases e.g. HIV binds at the edge

37
Q

What are Natural cytotoxicity receptors (NCRs)?

A

These provide activating signals to NK cells but are not well characterised.

  • NCR 1 binds viral haemagglutinin
  • NCR 2 binds a ligand that is expressed on tumour cells and upregulated during infection.
  • Ligand for MCR3 is a stress induced protein.
38
Q

What does target cell death or survival depend on?

A

Depends on balance of activating and inhibitory signals:

  • Inhibitory signals from KIR/MHC binding will lead to survival
  • Activation of killing from other signals leads to death
39
Q

Describe the action of antibody-dependent cell mediated cytotoxicity

A
  1. An infected cell will show antigens on the surface
  2. Antibodies will be able to bind to that
  3. Fc receptors on the NK cells will recognise the antibodies which activates the receptor
  4. This causes a strong signal which allows the NK to destroy the target
  5. This outweighs the inhibitory signal for MHC.
40
Q

Why do NK cells kill tumour cells?

A
  • Similar to pathogens: tumour cells escape the adaptive immune system by down regulating the expression of MHC-I.
  • This leads to no suppression of KIR and therefore, they become more susceptibile to NK cells.
41
Q

What is the mechanism of cytotoxic granules lysis?

A
  1. NK cells and T cells carry granules filled with cytotoxic proteins.
  2. The release of these is due to contact with the target cell.
  3. This is good as it ensures innocent healthy cells do not get damaged.
42
Q

How do CD8 cells trigger apoptosis?

A
  1. This process does not depende on cytotoxic granules.
  2. Fas ligand (FasL) on cytotoxic T cell engages with Fas on target cells to trigger the apoptotic pathway.
  3. This pathway is used to dispose unwanted lymphocytes
43
Q

What does loss of Fas result in?

A

It result in autoimmune lymphoproliferative syndrome (ALPS)

44
Q

Differences between NK cells and Cytotoxic T cells

A

NK cells:

  • NK receptor (numerours activating or inhibitory)
  • Ligand type is Class I MHC, MICA/B, immune complexes etc
  • The absence of class I MHC results in immediate cytotoxicity (“missing self”)
  • The presence of MHC class I results in inhibitory signal to NK cell.
  • No co-receptor
  • Invariant receptors with broader specificity for MHC allele subsets
  • Respond to the absence of MHC class I
  • Ready to act on encountering targets in the periphery
  • No memory

Cytotoxic T cells:

  • T cell receptor
  • Ligand is the peptide-MHC Class I complex
  • The absence of MHC class I results in lack of recognition.
  • The presence of MHC class I results in TCR engagement
  • Uses CD8 as a co-receptor
  • Unique receptors for a single MHC/peptide complex
  • Initial activation of naive T cells, followed by differentiation and proliferation required.
  • Memory responses

SEM 4: Immunology (15 decks)

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