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4.1 Transfusion and Transplant Immunology > Cytokines - T helper > Flashcards

Cytokines - T helper Flashcards

1
Q

What are the three signals involved in T cell activation?

A

The MHC-peptide-TCR interaction
Co-stimulation signal
Cytokine signal from the APC/microenvironment

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2
Q

It was originally thought that activation of naive helper-T cells resulted in what two outcomes, what controlls this?

A

Th1 cells or Th2 cells

They type depends on cytokine signals from the antigen presenting cell

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3
Q

What are Th1 cells, give an example of a response, when are they appropriate?

A

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

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4
Q

What are Th2 cells, give an example or a response, when are they appropriate?

A

T helper cells that promote humoral immunity

Eg. IgE production

They are appropriate in parasite infection and allergy

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5
Q

What cytokines are produced by Th1 cells and what do they do?

A

Pro-inflammatory cytokines:
- IFN-y
- IL-2

Responsible for cellular immunity through macrophage activation, CTL activation, opsoning IgG (opsonising antibodies good for bacterial infection)

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6
Q

What cytokines are produced by Th2 cells and what do they do?

A

Anti-inflammatory cytokines:
- IL4
- IL5

This are involved in humoral immunity
They decrease macrophages
They increase eosinophil activation
They increase IgG, IgE and IgA

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7
Q

What is the main role of Th1 cells in transplantation?

A

These cytokines drive cell-mediated graft rejection and macrophage infiltration

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8
Q

What is the main role of Th2 cytokines in transplantation?

A

These cytokines are involved in antiody-mediated graft rejection through eosinophil and mast cell production

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9
Q

What is the main role of Th2 cytokines in transplantation?

A

These cytokines are involved in antiody-mediated graft rejection through eosinophil and mast cell production

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10
Q

How are naive T cells stimulated to go down Th1 or Th2 pathways?

A

Naive -> IL-12 -> Th1

Naive -> IL-4 -> Th2

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11
Q

Talk about the positive feedback of both Th1 cell formation and Th2

A

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

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12
Q

What are the gene targets for Th1 and Th2 cells?

A

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

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13
Q

Talk about the negative feedback of the Th1/Th2 loop

A

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

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14
Q

What are regulatory T cells?

A

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+

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15
Q

Talk about the history of the Tregs

A

Discussed as early as the 1980s and 1990s
At first just a hypothetical cell called a surpressor cell
Wasnt identified until 15 years ago

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16
Q

What is CD25?

A

IL-2 receptor

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17
Q

Give an example of the role of T ehlper cells

A

Responsible for peripheral tolerance
Suppress Th1 and Th2
Defend the body against autoimmune conditions such as MS

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18
Q

Give an example of the role of T ehlper cells

A

Responsible for peripheral tolerance
Suppress Th1 and Th2
Defend the body against autoimmune conditions such as MS

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19
Q

How do Tregs mediate their effects?

A

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

20
Q

What would the presence of Tregs in a disease condition indicate?

A

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

21
Q

What are Th17 cells?

A

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

22
Q

What do Th17 cells do?

A

Produce IL-17
Recruit macrophages and neutrophils
- responsible for the stimulation of NETS and reactive oxygen species

23
Q

List three diseases that Th17 cells are involved in

A

Multiple sclerosis
Inflammatory bowel disease
Rheumatoid arthritis

24
Q

What rejection can TH17 cells be involved in?

A

Both acute and chronic

25
Q

What is the master transcription factor for Th17 cells?

A

RORyT

26
Q

What is the master transcription factor for Th17 cells?

A

RORyT

27
Q

What are the four pathways naive T cells can go down, with what stimulation?

A

TGF-B -> Treg (FoxP3+)
IFNy -> Th1 (STAT-1/T-bet+)
IL-4 -> Th2 (STAT-/GATA-3+)
TGF-B + IL-6 -> Th17

28
Q

What is IL17

A

potent pro-inflammatory cytokine)

29
Q

What do Treg cells produce, what is their role?

A

TGF-B (positive feedback)
IL-10

Tolerance + mainaining immune homeostasis

30
Q

What do Th1 cells produce, what is their role?

A

IFN-y

Immunity against intracellular pathogenes and autoimmuniy

31
Q

What do Th2cells produce, what is their role?

A

IL-4
IL-5
IL-13

Immunity against extracellular pathogens, allergy, atopy

32
Q

What do Th2cells produce, what is their role?

A

IL-4
IL-5
IL-13

Immunity against extracellular pathogens, allergy, atopy

33
Q

What do Th17 cells produce, what is their role?

A

IL-17
IL-21
Il-22

Immunity against extracellular pathogens and autoimmunity

34
Q

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

A

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

35
Q

What does PAMP stand for?

A

Pathogen associated molecular patterns

36
Q

What does PRR stand for?

A

Pattern recognition receptors

37
Q

During transplantation how are APCs stimulated and how do they inflluence naive T cells

A

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

38
Q

What are some examples of DAMPS?

A

Genomic DNA
Mitochondrial DNA
uric acid
Histones

39
Q

What will happen to the graft if Th1 cells are produced?

A

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

40
Q

What will happen to the graft if Th2 cells are produced?

A

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

41
Q

What will happen to the graft if Th17 cells are produced

A

Th-17 cells produce IL-17

IL-17 recruits neutrophils to the site of transplantation, reactive oxygen species produce

Promotes graft rejection

42
Q

What will happen to the graft if Tregs are produced?

A

Tregs produce Il-10 and TGF-B

Tolerance and graft survival

43
Q

Compare the stimulation of Tregs vs Th17, how can we utilise this in transplantation

A

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

44
Q

Talk about some ways in which Tregs have been utilised in transplantation

A

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

45
Q

What is CAR-T therapy

A

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

4.1 Transfusion and Transplant Immunology (24 decks)

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