7. Cytokine Signalling

Question 1

Cytokines are the main factors controlling mid- and long-range cell to cell communication
TRUE OR FALSE

Answer 1

TRUE

Question 2

Cytokines coordinate the immune response

TRUE OR FALSE

Answer 2

TRUE

Question 3

Cytokines define the type and duration of the elicited immune response
TRUE OR FALSE

Answer 3

TRUE

Question 4

Tumours change cytokine balance in the tumour micro-environment to manipulate the immune response:

Answer 4

Effective anti-tumour response: CD8 T cells and NK cells activated by cytokines such as IL-2, IL-12, and IFNgamma -> tumour clearance

Ineffective anti-tumour response: Tumour cells secrete cytokines that promote tumour growth via suppression of anti-tumour response, associated with factors such as IL-6, IL-10, and IL-4 and with CD4 Treg cells.

Question 5

Cytokine Signalling:

Answer 5

1. Cytokine binds to cell surface receptor
2. Brings receptor-associated JAK kinases into close proximity
3. Trans-phosphorylation of JAK kinases occurs, activating them
4. JAK kinases phosphorylate key Tyr residues in the receptors intracellular domains
5. pTyr residues act as docking sites for transcription factors of the STAT family (bind via SH2 domains)
6. JAK kinases then phosphorylate STATs
7. STATS dissociate from receptor and form dimers (both homo- and hetero-dimers)
8. STAT dimers translocate to nucleus and induce expression of genes

Question 6

JAKs bind cytokine receptors via BLANK domains

Answer 6

JAKs bind cytokine receptors via FERM-SH2 domains

Question 7

Different STAT pairs bind either BLANK OR BLANK sequences in the promote of responsive genes

Answer 7

Different STAT pairs bind either ISRE- or GAS- sequences in the promoter of responsive genes

Question 8

ISGF3 complex

Answer 8

STAT1, STAT2, and irf9 proteins, engages ISRE DNA elements

Question 9

GAS element bound by all STAT dimers except for the ISGF3 complex
TRUE OR FALSE

Answer 9

TRUE

Question 10

“Two-step binding” VS “Dimer rearrangement” modes of cytokine signalling:

Answer 10

Receptors must dimerise for signalling to occur.

So is dimerisation of receptors induced upon cytokine binding? “Two-step binding”

OR

Are receptors preformed as dimers in the absence of ligands? “Dimer rearrangement”

ANSWER = Both exist

Question 11

Cytokines can bind their receptors in 4 different interfaces:
[Give 4 interfaces]

Answer 11

Site1, Site2, Site3, and the Stem region of the receptor

Only site1 and site2 are conserved across the entire JAK/STAT cytokine receptor family

Question 12

Site 1 Properties:

Answer 12

• High affinity interface
• Very specific
• “Hot-Spots”: Hot spot AAs are residues whose mutation significantly changes the binding affinity of the ligand for its receptor, leads to high specificity

Question 13

Site 2 Properties:

Answer 13

• Low affinity interface
• Less specific
• Lacks Hot-spots, instead has surface complementarity interactions

Question 14

Stem Region properties:

Answer 14

• Only in some complexes

- Helps to stabilise the cytokine receptor-cytokine receptor complex