T cell differentiation, function and regulation

Question 1

What are the polarizing cytokines, master transcriptional regulator, effector cytokines, effector function and role in disease of Th2 cells?

Answer 1

• polarizing cytokines = IL-4
• master ts regulator = GATA3
• effector cytokines = IL-4, IL-5, IL-13 –> activate B cells
• effector functions = combats helminths infection and activated esosinophils
• role in disease = allergy

Question 2

What are the polarizing cytokines, master transcriptional regulator, effector cytokines, effector function and role in disease of Th1 cells?

Answer 2

• polarizing cytokines = IL-12, IFN-g, IL-18
• master ts regulator = T-Bet
• effector cytokines = IFN-g, TNF –> proinflammatory
• effector functions = combats intracellular pathogens and activates macrophages
• role in disease = tissue inflammation

Question 3

Describe the three processes that Th1 cell use to activate DCs

Answer 3

1. licensing of DCs to present to CD8+ T cells by CD40 activation
2. chemokines that recruit more inflammatory cells
3. cytokines that activate more inflmmatory cells via IFNg binding to IFNgR

Question 4

Why do Th1 cells activate macrophages? How do Th1 cells activate macrophages?

Answer 4

• Th1 are very important for clearing bactering that replicate inside macrophages (e.g. TB)
• signaling through CD40 and IFNgR promotes fusion of endosomes with lysosomes to promote killing of bacteria

Question 5

Describe how Th2 cells alternatively activate macrophages

Answer 5

IL-13 conditions macrophages to increase:
- Ag presentation
- co-stimulation, scavenger Rs (mannose R and dectin R) to fungal Ag.s
- chitinases to degrade fungal and insect chitin
- anti-flammatory cytokines such as IL-10 and factors (TGF-b) to promote would healing

Question 6

Describe the cross-regulation of Th1 and Th2 cells

Answer 6

• expression of one master ts regulator block expression of the other (T-Bet and GATA3 inhibit each other)
• e.g. if there’s lots of IL-4 and some IL-12 –> Th2

Question 7

Describe some general characteristics of Treg cells

Answer 7

• develop in the periphery
• secretes antiinflammatory cytokines
• tumor treatments = shutting down Treg cells

Question 8

Describe how Treg cells create tolerance responses?

Answer 8

1. express high levels of inhibitory CTLA-4 molecules that binds to CD80/86:
   - inhibit CD80/86 expression
   - increase IDO
   - decrease IL-6/TNFa (proinflammatory) production
2. absorb IL-2 using IL-2R
3. secrete antiinflammatory cytokines (IL-10 TGF-b) into the surrounding area, shutting down nearby cell’s reponses

Question 9

Tregs secrete IDO, what does it do?

Answer 9

breaks down tyr, tyr is critical for T cell activation

Question 10

What is the bystander suppression effect?

Answer 10

• a Treg that interacts with an APC can supress T cells that engage seperate MHC-II complexes on the APC surface
• “linked supression”

Question 11

What is an important site of functions for Tregs?

Answer 11

mucosal system

Question 12

What is Job syndrome, where is the defect located, what are some characterisitcs?

Answer 12

• Job syndrome = hyper IgE syndrome
• defect = mutation in STAT3
• recurrent skin and lung infections
• elevated IgE levels in serum
• unable to respond to IL-6 (trigger the function of Th17)

Question 13

Describe the cross-regulation of Th17 and pTreg cells

Answer 13

• TGF-beta is a key cytokine for the differntiation of both subsets
• IL-6 is the switch, allowing RORgT to dominate and induce Th17 subset and not Treg

Question 14

Why is a balance between Treg and Th17 cells ideal?

Answer 14

• normal state could favor development of suppressive Treg population to keep inflammation controlled
• inflammation from an infection (leading to IL-6 production) would stimulate more antibacterial Th17 differentiation

Question 15

What is leprosy? Describe and name the two forms of leprosy observed

Answer 15

• leprosy = bacteria replication inside macrophage vacuoles

tuberculoid:
- granulomas form and damage is limited to skin and nerves
- patient usually survives

lepromatous:
- extensive replication of bacteria
- fatal if untreated

Question 16

In leprosy, why does the same bacteria create different outcomes?

Answer 16

• Th1 responses are required to control m. leprae
• patients who developed lepromatous had a Th2 response instead of Th1

Question 17

What are CTL functions?

Answer 17

1. make IFNg and TNFa
   - antiviral
   - induce MHC-I expression
   - activate macrophages
2. induce death
   - cytotoxins (perforins and granzymes)
   - TNFa
   - FASL-FAS interactions

Question 18

Describe how CTLs induce cell death via degranulation, what proteins are important for production of an immune synapse?

Answer 18

1. CTL TCR+CD8 binds to target cell MHC-I+Ag
2. conjugate formation
3. CTL cytoplasmic rearrangement
4. CTL granules exocytose
5. dissociatoin
6. CTL recycling

• LFA-1-ICAM-1 interactions are vey important for degranulation

Question 19

How does the conformation of LFA-1 change when a CTL is activated?

Answer 19

• inactive = low affinity LFA-1 (lying down)
• active = high affinity LFA-1 (standing)

Question 20

How are CTLs protected from perforin?

Answer 20

• cathepsin B is a memb-bound protease that is located in the granules that contain perforin and granzymes
• during degranulation, cathepsin B gets to the cell surface and degrades perforin that stays near the CTL membrane

Question 21

How do CTLS induce cell death through memb-bound TNFa?

Answer 21

mTNFa binds to TNFR1 on target cells and causes programmed cell death

Question 22

How do CTLS induce cell death through FAS activation?

Answer 22

• FasL on CTL interacts with FAS on the target cell
• activates downsream signals through a series of caspases
• induces apoptosis

Question 23

Describe what occurs to end the T cell response

Answer 23

1. Tregs decrease T cell activity
2. co-inhibitory R’s (CTLA4, PD-1) are upregulated
3. activation-induced cell death (AICD)

Question 24

Describe some characterisitcs of CTLA-4

Answer 24

• expressed 24 hours after naive cells are activated
• expressed at lower levels than CD28
• binds to CD80/86 with greater affinity than CD28

Question 25

Describe the effects of PD-1 signaling

Answer 25

1. limits proliferation 2. limits cytokine production 3. limits cytotoxicity

Question 26

Describe how AICD is triggered

Answer 26

1. when naive T cells are activated they upregulate FAS, FASL and have high BCl-Xl levels 2. if there is lack of Ag stimulation and cytokines, Bcl-Xl decreases and FASL trimerizes 3. T cells trigger apoptosis in each other

Question 27

What is Canale-Smith syndrome: how is it caused, what does it cause?

Answer 27

- caused by defective FAS-FASL - causes lymphoproliferative diseases

Question 28

What are FAS-FASL interactions important for in terms of reducing T cell activity?

Answer 28

1. peripheral deletion of autoreactive T cells 2. limiting T cell expansion 3. shutting down T cell response