Cytokines - T helper Flashcards
What are the three signals involved in T cell activation?
The MHC-peptide-TCR interaction
Co-stimulation signal
Cytokine signal from the APC/microenvironment
It was originally thought that activation of naive helper-T cells resulted in what two outcomes, what controlls this?
Th1 cells or Th2 cells
They type depends on cytokine signals from the antigen presenting cell
What are Th1 cells, give an example of a response, when are they appropriate?
Helper T cells which produce cytokine products which promotre cell-mediated immunity
Macrophage activation and T cel activation
Appropriate in intracellular pathogen eradication e.g. viruses and bacteria
What are Th2 cells, give an example or a response, when are they appropriate?
T helper cells that promote humoral immunity
Eg. IgE production
They are appropriate in parasite infection and allergy
What cytokines are produced by Th1 cells and what do they do?
Pro-inflammatory cytokines:
- IFN-y
- IL-2
Responsible for cellular immunity through macrophage activation, CTL activation, opsoning IgG (opsonising antibodies good for bacterial infection)
What cytokines are produced by Th2 cells and what do they do?
Anti-inflammatory cytokines:
- IL4
- IL5
This are involved in humoral immunity
They decrease macrophages
They increase eosinophil activation
They increase IgG, IgE and IgA
What is the main role of Th1 cells in transplantation?
These cytokines drive cell-mediated graft rejection and macrophage infiltration
What is the main role of Th2 cytokines in transplantation?
These cytokines are involved in antiody-mediated graft rejection through eosinophil and mast cell production
What is the main role of Th2 cytokines in transplantation?
These cytokines are involved in antiody-mediated graft rejection through eosinophil and mast cell production
How are naive T cells stimulated to go down Th1 or Th2 pathways?
Naive -> IL-12 -> Th1
Naive -> IL-4 -> Th2
Talk about the positive feedback of both Th1 cell formation and Th2
Th1:
IL-12 converts naive T cells into Th1 cells -> Th1 cells produce IFN-y -> IFNy positively stimulates Th1 differentiation
Th2:
IL4 converts naive T cells into Th2 cells -> Th2 cells produce Il4 -> thus increasing the amount of Th2 cells
What are the gene targets for Th1 and Th2 cells?
Th1 = T-bet
Th2 = GATA3
These cells produce these specific transcription factors and are thusly used to identify these cells -> can do intracellular staining etc
Talk about the negative feedback of the Th1/Th2 loop
The products of either Th1 cells or Th2 cells block the production of the opposite cell
Th1 cells produce IFN-y which blocks Th2 production
Th2 cells produce IL4 and Il% while blocks Th1 production
What are regulatory T cells?
T cells expressing CD4 and CD25
They mediate peripheral tolerance
They suppress Th1 and Th2 cells
They are antigen specific
Their master transcription factor is FoxP3
They are defined as being CD3+CD4+CD25+FoxP3+
Talk about the history of the Tregs
Discussed as early as the 1980s and 1990s
At first just a hypothetical cell called a surpressor cell
Wasnt identified until 15 years ago
What is CD25?
IL-2 receptor
Give an example of the role of T ehlper cells
Responsible for peripheral tolerance
Suppress Th1 and Th2
Defend the body against autoimmune conditions such as MS
Give an example of the role of T ehlper cells
Responsible for peripheral tolerance
Suppress Th1 and Th2
Defend the body against autoimmune conditions such as MS
How do Tregs mediate their effects?
Tregs express CTLA-4 which can bind CD28 and prevent immune response -> prevents activation of T cells
Tregs express CD25 (IL-2) receptors -> these can be used to mop up any IL2 and thus prevents T cell activation
Tregs can kill autoreactive T cells through the use of cytotoxic granules
Tregs produce TGFB and IL-10 which suppresses TH17 cell responses
What would the presence of Tregs in a disease condition indicate?
It is often hard to know if the Treg activity is causing the disease or is beacuse of the disease (trying to suppress etc)
This is oftn the case for autoimmune conditions where homing of Tregs is evident
What are Th17 cells?
T helper subset of cells
They are pro-inflammatory
They are shown to be elevated in many autoimmune inflammatory conditions
They are known to contribute to acute and chronic graft rejection
What do Th17 cells do?
Produce IL-17
Recruit macrophages and neutrophils
- responsible for the stimulation of NETS and reactive oxygen species
List three diseases that Th17 cells are involved in
Multiple sclerosis
Inflammatory bowel disease
Rheumatoid arthritis
What rejection can TH17 cells be involved in?
Both acute and chronic
What is the master transcription factor for Th17 cells?
RORyT
What is the master transcription factor for Th17 cells?
RORyT
What are the four pathways naive T cells can go down, with what stimulation?
TGF-B -> Treg (FoxP3+)
IFNy -> Th1 (STAT-1/T-bet+)
IL-4 -> Th2 (STAT-/GATA-3+)
TGF-B + IL-6 -> Th17
What is IL17
potent pro-inflammatory cytokine)
What do Treg cells produce, what is their role?
TGF-B (positive feedback)
IL-10
Tolerance + mainaining immune homeostasis
What do Th1 cells produce, what is their role?
IFN-y
Immunity against intracellular pathogenes and autoimmuniy
What do Th2cells produce, what is their role?
IL-4
IL-5
IL-13
Immunity against extracellular pathogens, allergy, atopy
What do Th2cells produce, what is their role?
IL-4
IL-5
IL-13
Immunity against extracellular pathogens, allergy, atopy
What do Th17 cells produce, what is their role?
IL-17
IL-21
Il-22
Immunity against extracellular pathogens and autoimmunity
During an infection how do the APCs know what cytokines to present to Naive T cells to produce the right kind of T helper respose
Pathogen associated molecular patterns (PAMPS) are detected by Pathogen recognition receptors (PRRs) on an APC
This results in the activation of the APC as well as the production of its cytokines
The engagement of different PRRs results in the production of different cytokines e.g. viral PAMPs promote cell-mediated immunity as theyre intracellular but encapsulated bacterial PAMPs promote humoral immunity as they are extracellular
What does PAMP stand for?
Pathogen associated molecular patterns
What does PRR stand for?
Pattern recognition receptors
During transplantation how are APCs stimulated and how do they inflluence naive T cells
Tissue damage and hypoxia result in release of damage-associated molecular patterns (DAMPs)
DAMPs engage PRR and promote either Th1, Th2 or Th-17 responses
What are some examples of DAMPS?
Genomic DNA
Mitochondrial DNA
uric acid
Histones
What will happen to the graft if Th1 cells are produced?
Th1 cells will produce IFNy
IFNy promotes macrophage activation, CD8+ activation and IgG2a production by B cells
IgG2a can activate complement
All of these contribute to rejection of the graft
What will happen to the graft if Th2 cells are produced?
Th2 cells will produce IL-4, IL-5, IL-9, IL-10 and IL-13
These interleukins will activate B cells (DSAs) and eosinophils (IL5)
These will promote graft rejection
What will happen to the graft if Th17 cells are produced
Th-17 cells produce IL-17
IL-17 recruits neutrophils to the site of transplantation, reactive oxygen species produce
Promotes graft rejection
What will happen to the graft if Tregs are produced?
Tregs produce Il-10 and TGF-B
Tolerance and graft survival
Compare the stimulation of Tregs vs Th17, how can we utilise this in transplantation
TGFB needed for Tregs
TGFB + IL6 forms Th17 cells
We use drugs such as Tocilizumab which is anti-IL6 to prevent Th17 cell formation and boost Treg formation
Talk about some ways in which Tregs have been utilised in transplantation
1: Enrich for Tregs in PBMC, removal of patient Tregs, ex-vivo expansion, IL2 and TCR stimulation to bring about non specific polyclonal expansion, and reinfusion -> large amount of Tregs but not antigen specific
2: Donor PBMC mixed with recipient Tregs -> donor specific Tregs result -> expand these ex-vivo and reinfuse -> results in specific donor AllAg-reactive Treg populations
Unfortunately immunosuppressents are still needed but there is a lot of research ongoing for this
Studies are still small and early on but Tregs did generally support survival of grafts with no side effects
What is CAR-T therapy
Chimeric Antigen Receptor Tregs
Engineered Tregs to target alloantigens and suppress anti-graft responses in the recipient
Redirecting Tregs towards mismatched donor HLA molecules by modifying them with chimeric antigen receptors to render Tregs far more effective at preventing rejection
These cells are highly antigen specific and show superior homing capacity to allografts compared to polyclonal Tregs
Method of actively suppressing mismatched HLA rejection
Attractive compared to pan immunosuppressives as were only taregetting cells attacking our graft not all immune cells
