T cell differentiation, function and regulation Flashcards
What are the polarizing cytokines, master transcriptional regulator, effector cytokines, effector function and role in disease of Th2 cells?
- 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
What are the polarizing cytokines, master transcriptional regulator, effector cytokines, effector function and role in disease of Th1 cells?
- 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
Describe the three processes that Th1 cell use to activate DCs
- licensing of DCs to present to CD8+ T cells by CD40 activation
- chemokines that recruit more inflammatory cells
- cytokines that activate more inflmmatory cells via IFNg binding to IFNgR
Why do Th1 cells activate macrophages? How do Th1 cells activate macrophages?
- 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
Describe how Th2 cells alternatively activate macrophages
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
Describe the cross-regulation of Th1 and Th2 cells
- 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
Describe some general characteristics of Treg cells
- develop in the periphery
- secretes antiinflammatory cytokines
- tumor treatments = shutting down Treg cells
Describe how Treg cells create tolerance responses?
- 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 - absorb IL-2 using IL-2R
- secrete antiinflammatory cytokines (IL-10 TGF-b) into the surrounding area, shutting down nearby cell’s reponses
Tregs secrete IDO, what does it do?
breaks down tyr, tyr is critical for T cell activation
What is the bystander suppression effect?
- a Treg that interacts with an APC can supress T cells that engage seperate MHC-II complexes on the APC surface
- “linked supression”
What is an important site of functions for Tregs?
mucosal system
What is Job syndrome, where is the defect located, what are some characterisitcs?
- 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)
Describe the cross-regulation of Th17 and pTreg cells
- 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
Why is a balance between Treg and Th17 cells ideal?
- 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
What is leprosy? Describe and name the two forms of leprosy observed
- 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
In leprosy, why does the same bacteria create different outcomes?
- Th1 responses are required to control m. leprae
- patients who developed lepromatous had a Th2 response instead of Th1
What are CTL functions?
- make IFNg and TNFa
- antiviral
- induce MHC-I expression
- activate macrophages - induce death
- cytotoxins (perforins and granzymes)
- TNFa
- FASL-FAS interactions
Describe how CTLs induce cell death via degranulation, what proteins are important for production of an immune synapse?
- CTL TCR+CD8 binds to target cell MHC-I+Ag
- conjugate formation
- CTL cytoplasmic rearrangement
- CTL granules exocytose
- dissociatoin
- CTL recycling
- LFA-1-ICAM-1 interactions are vey important for degranulation
How does the conformation of LFA-1 change when a CTL is activated?
- inactive = low affinity LFA-1 (lying down)
- active = high affinity LFA-1 (standing)
How are CTLs protected from perforin?
- 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
How do CTLS induce cell death through memb-bound TNFa?
mTNFa binds to TNFR1 on target cells and causes programmed cell death
How do CTLS induce cell death through FAS activation?
- FasL on CTL interacts with FAS on the target cell
- activates downsream signals through a series of caspases
- induces apoptosis
Describe what occurs to end the T cell response
- Tregs decrease T cell activity
- co-inhibitory R’s (CTLA4, PD-1) are upregulated
- activation-induced cell death (AICD)
Describe some characterisitcs of CTLA-4
- expressed 24 hours after naive cells are activated
- expressed at lower levels than CD28
- binds to CD80/86 with greater affinity than CD28
Describe the effects of PD-1 signaling
- limits proliferation
- limits cytokine production
- limits cytotoxicity
Describe how AICD is triggered
- when naive T cells are activated they upregulate FAS, FASL and have high BCl-Xl levels
- if there is lack of Ag stimulation and cytokines, Bcl-Xl decreases and FASL trimerizes
- T cells trigger apoptosis in each other
What is Canale-Smith syndrome: how is it caused, what does it cause?
- caused by defective FAS-FASL
- causes lymphoproliferative diseases
What are FAS-FASL interactions important for in terms of reducing T cell activity?
- peripheral deletion of autoreactive T cells
- limiting T cell expansion
- shutting down T cell response
