L21 - Natural Born Killers: NK Cells & CD8+ T-Cells

Question 1

Where do NK cells originate form

Answer 1

they are a subset of innate lymphoid cells which come from common lymphoid progenitor cell

Question 2

What are the role of Cytotoxic Lymphocytes?

Answer 2

They destroy:

• cells infected with bacteria, viruses or parasites.
• tumour cells
• able to detect changes in protein production inside the target cell

Question 3

Why do we need more than one type of cytotoxic lymphocyte?

Answer 3

1. To combat infection in the period before a T cell response develops
2. To provide an alternative system when a tumour or infected cells evade Cytotoxic T cell responses
3. To provide an additional mechanism for killing infected targets via antibody recognition

Question 4

What is the role of MHC class 1

Answer 4

Lymphocytes scanning a target cell surface need to detect changes in protein production inside that target cell

MHC class I proteins are found at the cell surface

Form a structure that presents protein fragments (peptides) at the cell surface for immune surveillance

Recognised by CD8+ cytotoxic T cells

Question 5

How are intracellular proteins presented at the surface by MHC class 1?

Answer 5

• virus infects cell
• viral proteins synthesised in cytoplasm
• peptide fragments of viral proteins bound by MHC class 1 in ER
• Bound peptides transported by MHC class 1 to the cell surface
• cytotoxic T cell recognise complex of viral peptide and kills infected cell.

Question 6

Describe the structure of MHC class 1?

Answer 6

Peptide binding cleft (2 alpha helices with beta sheet) = to bind peptide

Beta 2 micro-globulin = bottom part/ supportive framework

Question 7

Why do we have HLA Polymorphism?

Answer 7

Pathogens can evolve to evade the immune response

variation in MHC class 1 proteins , multiple genes and high genetic variability within these genes may counteract this problem

Question 8

Where are polymorphisms on MHCs located?

Answer 8

Found within the peptide binding groove

Question 9

In terms of MHC class 1, what does the T-cell receptor recognise?

Answer 9

TCR recognises both the MHC protein and the peptide antigen being presented by it

Question 10

Where does CD8 and TCR bind on MHC?

Answer 10

TCR binds to the a1a2 domains

CD8 binds to the support domains (a3 and b2m)

Question 11

what is the function of killer Ig-like (KIR) receptors?

Answer 11

They are on the surface of NK cells.

Some viruses down-regulate MHC 1 to evade cytotoxic T-cells.
If KIR binds to MHC, it stops NK cells from releasing lytic granules. If there is No KIR inhibition then lytic granules are released

Question 12

What are Natural Cytotoxity Receptors?

Answer 12

These provide activating signals to NK cells, but their range of ligands are not well characterised

EG:
NKp46 is known to bind viral hemagglutinin

NKp44 – binds a ligand that is expressed on tumor cells and up-regulated by viral infection

Question 13

Describe ADCC?

Answer 13

Antibody-dependent cell-mediated cytotoxity

NK cells express a receptor that recognizes the Fc portion of antibodies

This receptor delivers a strong activating signal when it recognizes antibodies bound to a cell surface

Results in lysis of the target cell

Question 14

Describe Cytotoxic granules as a mechanism of lysis

Answer 14

NK cells and T cells carry granules filled with cytotoxic proteins
Release cytotoxic granules at site of contact with target cell
(must be directed in order to avoid damaging innocent bystander cells)

Question 15

What does Perforin do?

Answer 15

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

Question 16

What does Granzymes do?

Answer 16

Serine proteases, which activate apoptosis once in the cytoplasm of the target cell

Question 17

What does Granulysin do?

Answer 17

Has antimicrobial actions and can induce apoptosis

Question 18

What is the Immunological Synapse?

Answer 18

T cell receptors and co-receptors cluster at the site of cell-cell contact

This polarises the T cell to release effector molecules at the point of contact

Question 19

Describe how the Fas/FasL interaction leads to cell death?

Answer 19

Fas ligand (FasL) on T cells engages Fas on target cells to trigger apoptotic pathway

Fas/FasL triggered apoptosis is used to dispose of unwanted lymphocytes

Loss of Fas can result in autoimmune lymphoproliferative syndrome (ALPS)

Question 20

Compare the differences between Cytotoxic T-cells wth Natural killer cells?

Answer 20

CYTOTOXIC T-CELLS:

• Use CD8 as a co-receptor for MHC class I
• Each express a unique and highly specific T cell receptor with CD8 acting as a co-receptor
• Presence of appropriate MHC class I ligand results in activation of killing response
• Absence of appropriate MHC class I ligand – no recognition and cell moves on
• Response requires initial activation of naïve T cells, followed differentiation and proliferation

NATURAL KILLER CELLS:

• Do not use a co-receptor for MHC class I, do not express CD8
• Express multiple receptors including activating receptors and inhibitory receptors
• Presence of appropriate MHC class I ligand results in inhibition of killing
• Absence of appropriate MHC class I ligand results in activation of killing response
• Ready to act on encountering targets in the periphery