Costim and IL-2

Question 1

what do T cells need when they are activated

Answer 1

to survive
proliferate quickly
upregulate metabolism
acquire functions

Question 2

what is the initial role of TCR?

Answer 2

to get Il-2 made and respond to IL-2

Question 3

what is the role of IL-2?

Answer 3

to drive the essential functions of T cell that are required after proliferation

Question 4

what is the role of costimulatory receptors CD28 and CD80?

Answer 4

sends an extra activation signal

Question 5

what happens when PLCg is activated?

Answer 5

Leads to three pathwyas that activate distinct transcripton factors

Question 6

how does co-stimulatory signalling lead to PLCg activation?

Answer 6

CD28 signal leads to activation of PLCg

Signal 1: TCR signal -> recruitment of PLCg
Signal 2: costimulation signal -> activation of PLCg

Question 7

what happens when PLCg as activated?

Answer 7

goes into the nucleus

Question 8

how is PI3-kinase activated?

Answer 8

binds to phosphorylated CD28 and gets activated

Question 9

what happens when PI3-kinase is activated?

Answer 9

Activated PI3-kinase leads to recruitment of Itk

Question 10

what is the role of IP3?

Answer 10

IP3 increases intracellular Ca2+ concentration
This activates calcineurin
Calcineurin activates NFAT (transcription factor)

Question 11

what is the first role of DAG?

Answer 11

DAG recruits protein kinase C-Ø
protein kinase C-Ø activates CARMA
CARMA leads to activation of NFkappaB (transcription factor)

Question 12

what is the second role of DAG?

Answer 12

DAG recruits RasGRP
RasGRP activates Ras
Ras activates MAP kinase cascade
MAPK activates Fos, components of AP-I (transcription factor)

Question 13

what does TCR activation lead to?

Answer 13

IL-2 production

Question 14

what is the flow of TCR activation?

Answer 14

Second messenger
Pathway
Transcription factor
Target genes

Question 15

what does IL-2 control?

Answer 15

-survival
-proliferation
-metabolism
-cytotoxicity
-cytokine production
-T cell death

Question 16

what cells make polarizing cytokines?

Answer 16

dendritic cells

Question 17

what expressed IL-2?

Answer 17

activated T cells

Question 18

what are the features of IL-2?

Answer 18

Like all cytokines, IL-2 functions by receptor binding
IL-2 is shaped to allow interaction with two receptor chains

Question 19

what is the structure of the IL-2 receptor?

Answer 19

IL-2Ralpha
- up-regulated on activation
IL-Rbeta
- always present
- responsible for signal transduction
IL-2Rg
- responsible for signal transduction

Question 20

what is the structure of low affinity IL-2 receptor?

Answer 20

IL-2Ralpha only

Question 21

what is the structure of intermediate affinity IL-2 receptor?

Answer 21

IL-2Rbeta + gamma c

Question 22

what is the structure of high affinity IL-2 receptor?

Answer 22

IL-2alpha + IL-2beta + gamma c

Question 23

when does IL-2 send functional signals?

Answer 23

IL-2 functionally signals through intermediate or high affinity receptors only

Question 24

how are different affinity receptors formed?

Answer 24

1. IL-2 interacts with IL-2R alpha
2. conformational change in IL-2 that allows it to interact with IL-2R beta
3. gamma c is recruited
4. IL-2 binding leads to dimerisation of IL-2R beta and gamma c
5. dimeristion is required for signalling

Question 25

what are the IL-2 signalling pathways?

Answer 25

1. JAK-STAT pathway 2. RAS-MAP kinase pathway 3. PI3K pathway

Question 26

what is the JAK-STAT signalling pathway?

Answer 26

-No intrinsic protein kinase domains - Rely on Janus family kinases (JAKs) to initiate signalling - JAK activation leads to phosphorylation of IL-2R beta - SH2 domains of STAT proteins bind to phosphorylated receptors - STATs get phosphorylated, dimerise, translocate to nucleus

Question 27

what is the IL-2, IL-2R autocrine loop?

Answer 27

TCR activation via TCR and costimulation -> activation of NFAT NFkappaB AP1 -> expression of IL-2 and IL-2Ralpha chains IL-2 binds to IL-2R alpha chain Initiates IL-2 signalling Activation of STATs Expression of IL-2 and IL-2R

Question 28

how are T cells activated by IL-2?

Answer 28

Need IL-2 for proliferation and activation Need sustained IL-2 production -TCR signal up-regulates IL-2 and IL-2R alpha (via NFkappaB, NFAT, AP1) - IL-2 signalling up-regulates IL-2 and IL-2R alpha via STAT5

Question 29

what is the negative feedback of IL-2?

Answer 29

-signals via TCR change upon antigen clearance (via DCcs) - Signalling pathways in the T cell are different (two signalling pathways, SOCS, PTEN/BLIMP)

Question 30

how do SOCS act on IL-2 production?

Answer 30

Many cytokines self-regulate by expressing socs proteins SOCS are induced by STAT activation Inhibit cytokine signalling after the cytokine has had its effect

Question 31

what are SOCS?

Answer 31

Suppressor of cytokine signallinh

Question 32

how does PTEN and PLIMP-1 regulate IL-2?

Answer 32

IL-2 induces PRDM1 gene that encodes BLIMP-1 -BLIMP-1 is a transcription factor - BLIMP-1 represses IL-2 transcription - this stops the feedback loop

Question 33

what are the differences between IL-2 regulation via SOCS and BLIMP-1?

Answer 33

SOCS inhibits IL-2 production by interfering with te signalling pathway BLIMP-1 inhibits IL-2 production by suppressing the transcription of IL2