Topic 5

Question 1

What are the major roles that Th17 cells may play?

Answer 1

They may serve as a major therapeutic target for inflammatory diseases and they appear to be crucial for the maintenance of gut/immune homeostasis

Question 2

What are the common points across Th developmental pathways?

Answer 2

Master transcriptions factors which are switched on to further enhance differentiation
Signalling transducer and activator of transcription these are transcription factors required for Th development
Autocrine feedback loops which sustain and enhance specific Th responses

Question 3

What is the cytokine which provides the autocrine feedback loop for Th1 cells?

Answer 3

IFN-gamma

Question 4

What is the cytokine which provides the autocrine feedback loop for Th2 cells?

Answer 4

IL-4

Question 5

What is the cytokine which provides the autocrine feedback loop for Th17 cells?

Answer 5

IL-21

Question 6

What are the key players in Th1 differentiation?

Answer 6

IFN-Gamma and IL-12 begin the differentiation process via the IL-12 receptor to activate T-bet and pSTAT4 leading to the up regulation IL-18R

Question 7

What are the key players in Th2 differentiation?

Answer 7

IL-4 and IL-12 begin the differentiation process acting through an unknown receptor to activate GATA3 and Pstat5 to upregulate the IL-33R

Question 8

What are the key players in Th17 differentiation?

Answer 8

TGFBeta and IL-6 or IL-21 can initiate differentiation acting through the IL-23 receptor to activate RORgammat and pSTAT3 leading to the upregulation of IL-1R

Question 9

What is the 3 step model for Th17 cell development?

Answer 9

Naïve T cells are prompted to enter the Th17 cell pathway through either TGFBeta and IL-6 or TGFBeta and IL-21
This activates RORgammaT and STAT3 leading to IL-17 expression and amplification of the cell population as well expression of IL-23R this allows IL-23 to stabilize the Th17 cell population and induces the expression of the cytokines IL-17A, IL-17F and IL-22

Question 10

What cells can produce IL-6?

Answer 10

DC’s, monocytes, macrophages, mast cells, B cells, subsets of activated T cells, Tumour cells, Tumour cells, fibroblasts, endothelial cells, keratinocytes

Question 11

What can induce the expression of IL-6?

Answer 11

IL-1, TNF, PDGF, IL-3, GM-CSF, IL-17

Question 12

How does IL-21 influence Th17 cells?

Answer 12

It is produced by activated T cells, NK cells but not antigen presenting cells
It is important for the expansion of activated B cells and class switching
It is induced by IL-6 and IL-21
Its expression is dependent on STAT3 alone and it can allow the alternative pathway of Th17 cell differentiation

Question 13

Why is IL-23 essential for Th17 cells?

Answer 13

IL-23R is expressed on activated/memory T cell population

Promotes the production of IL-17, IL-1, TNF, IL-6 production by innate immune cells

Question 14

What occurs in the regulatory interplay between Th1, Th2 and Th17 cells?

Answer 14

Th1 and Th2 cells can negatively regulate each other and Th17 cells while Th17 cells are not able to negatively regulate any other subtype
This shows how these cells are relatively easy to turn off, possibly reflecting their potency

Question 15

What is the effect of Il-17 on endothelial cells?

Answer 15

This leads to the production of tissue factor, IL-6 and IL-8 leading to inflammation and potentially thrombosis

Question 16

What is the effect of IL-17 on epithelial cells and fibroblasts?

Answer 16

Expression of IL-6, IL-8, CCL20, G-CSF and GM-CSF promoting inflammation

Question 17

What is the effect of IL-17 on macrophages or dendritic cells?

Answer 17

Expression of IL-1, TNF and IL-6 which can promote inflammation as well as expression of MMPs which can cause cartilage damage

Question 18

What is the effect of IL-17 on chondrocytes?

Answer 18

Expression of nitric oxide which can lead to cartilage damage

Question 19

What is the effect of IL-17 on oesteoblasts?

Answer 19

Induction of RANKL which can induce oesteoclasotgenesis leading to bone erosion

Question 20

What is the role of IL-22R in Th17 cell function?

Answer 20

This is a heterodimeric receptor which contains IL-22R and IL-10R2, while IL-10R2 is ubiquitously expressed, IL-22 is limited to cells in the pancreas, kidney, colon, small intestine and liver
It is found on endothelial and epithelial cells rather than immune cells and thus allows Th17 cells to communicate with tissues

Question 21

What is the function of IL-21?

Answer 21

B cell differentiation, Ig class switching
Differentiation and cytotoxic program

Question 22

What is the function of IL-22?

Answer 22

Production of beta-defensins, epidermal hyperplasia, acute phase reactants

Question 23

What is the function of IL-17A/F?

Answer 23

Induction of Cytokines, chemokines, and inflammatory mediators and recruitment of immune cells to the site of inflammation

Question 24

What is the function of CCL20?

Answer 24

Recruitment of cells to the site of inflammation

Question 25

What is the role of Th17 cells in host defence?

Answer 25

They can allow activation and release of antimicrobial peptides and aid in barrier function

Question 26

How common are Th17 cells relative to other immune cell populations?

Answer 26

Only 1% of healthy human CD4+ cells are IL-17 producing though numbers can increase dramatically in pathological environments A large number of these memory cells have a specificity to fungal antigens

Question 27

What are the consequences of a lack of Th17 cells?

Answer 27

Recurrent, persistant infections of the skin, nails, oral and genital mucosae This has led to the suggestion that Th17 cells are required for the clearance of pathogens which require huge inflammatory responses

Question 28

What is the type of pathogen which Th17 cells may be specialized at dealing with?

Answer 28

Those which require a huge inflammatory response as Th17 cells are capable of rapidly inducing inflammation in mucosal tissues

Question 29

How do Commensal bacteria shape T cell resident homeostasis?

Answer 29

These bacteria coat epithelial surfaces such as skin, airways, gut and genital mucosa They contribute to immune surveillance through helping to maintain a balanced population of Th17, Th1 and Treg cells

Question 30

What are the potential consequences of commensal specific memory T cells?

Answer 30

They could provide cross-reactive protective responses to pathogens However they could also contribute to altered barrier integrity and the development of autoimmune inflammatory conditions such as IBD and psoriasis

Question 31

What are the tools which can be used for targeting the IL-17, Th17 pathway?

Answer 31

Inhibitors can be used to prevent Th17 cell generation such as inhibitors of RORC, STAT3 and IL-23 antibodies Il-17 or its receptor may be targeted with antibodies

Question 32

What is halofuginone?

Answer 32

This inhibits mouse/human Th17 cell differentiation by activating amino acid starvation response a cytoprotective signalling pathway. It can protect against experimental autoimmune encephalomyelitis

Question 33

What is digoxin?

Answer 33

This inhibits ROR-GammaT and thus inhibits murine Th17 cell differentiation without affecting other lineages and leads to reduced severity of EAE mice

Question 34

What is leukaemia inhibitory factor?

Answer 34

This can ameliorate EAE by selectively inhibiting pathogenic Th17 differentiation

Question 35

What are the characteristics of terminally differentiated Th17 cells?

Answer 35

The memory phenotype is long-lived, resistant to apoptosis and with a high capacity for expansion, they ensure maintenance of a constant repertoire of memory Th17 cells for a human life time despite finite life of individual effector cells and reduced thymus function They can mediate or promote long term-antitumour immunity Show plasticity and can be transdifferentiated into Th1and Th2 under specific conditions Manipulation of Th17 apoptosis and survival may be of therapeutic interest

Question 36

How do Th17 cells have plasticity?

Answer 36

CD4 cells can de or re differentiate with deletion of master regulators allowing phenotypic change through it is possible that differentiation may vary between in vivo and in vitro experiments It is possible that a partial rather than complete polarisation of a phenotype may be the norm in vivo

Question 37

What change in differentiation is induced by GATA3?

Answer 37

Allows Th2 cells to produce IFN-gamma

Question 38

What change in differentiation is induced by a reduction of FOXP3?

Answer 38

Reduction of this in Tregs results in a Th2 phenotype

Question 39

What is the role of Th17 cells in cancer?

Answer 39

They are a sign of a positive prognosis, particularly for patients with advanced disease

Question 40

What evidence shows that Th17 cells are required for disease in a mouse model of colitis?

Answer 40

In Dextran Sodium sulfate model mice it was found that the symptoms of disease as well as the expression of IL-6, TNF-alpha, IL-17, IL-17F, MCP-1 and RORgammaT were all reduced in IL-21 knockout mice

Question 41

What is Psoriasis?

Answer 41

Affects approximately 2% of the population and has a complex aetiology which likely contains a genetic component which could be activated by various environmental and infectious triggers

Question 42

What is the role of IL-17 in Psoriasis?

Answer 42

It acts on keratinocytes to produce innate defense proteins and chemokines that promote inflammation. These effects are amplified through TNF

Question 43

What are the anti-IL-17 agents currently being trialled for Psoriasis?

Answer 43

Brodalumab which targets IL-17R with 82% of patients on highest doses which achieves over 75% from baseline PASI 75= is the current gold standard and 62% of patients achieved a PASI 100 (complete clearance)

Question 44

What is the effect of a high salt diet on development of EAE?

Answer 44

High salt diets seem to boost the induction and activation of Th17 cells