Lecture 8 - Functional differentiation of effector T helper subsets

T-helper cell differentiation into specialist subsets is called what?

Polarisation

Naive T helper cells only produce which cytokine?

IL-2

What are the two forms of leprosy?

Tuberculoid

• Low infectivity

Lepromatous

• High infectivity

What type of response is generated in tuberculoid leprosy?

Mainly a Th1 response.

• Normal T-cell responsiveness to infection

What type of response is generated in lepromatous leprosy?

Mainly a Th2 response.

• Low/absent T-cell responsiveness to infection

What are the signature cytokines of Th1 cells?

IFN-gamma

TNF-beta

IL-2

What are the functions of Th1 cells?

• Activate macrophages

• Activate NK cells

• Enhance cytotoxic T-cell response

• Help B-cells with opsonising antibodies

What do Th1 cells protect against?

Intracellular parasites

Organ-specific autoimmunity is associated with which T helper subset?

Th1 cells

What are the signature cytokines of Th2 cells?

IL-4

IL-5

IL-13

What are the functions of Th2 cells?

• Activate mast cells/eosinophils

• Help B-cells with isotype switching to IgE

What do Th2 cells protect against?

Extracellular pathogens

Type I allergy is associated with which T helper subset?

Th2 cells

How are Th2 cells involved in type I allergy?

• Mite enzyme Der p 1 cleaves occludin in tight junctions and enters the mucosa 

• Der p 1 is presented by APCs to Th2 cells

• Th2 cell induces B-cell switch to IgE production

• IgE binds to FceRI receptors on mast cells

• Triggers mast cell degranulation.

• Granule contents cause allergic symptoms

What are the signature cytokines of Th17 cells?

IL-17a

IL-17f

IL-22

What are the functions of Th17 cells?

• Activation and recruitment of neutrophils

• Induction of pro-inflammatory mediators

  • IL-1beta

  • MMPs

  • PGE2

What do Th17 cells protect against?

Fungi and extracellular bacteria

Chronic inflammatory disease is associated with which T helper subset?

Th17 cells

What are the signature cytokines of Tfh cells?

IL-21

What are the functions of Tfh cells?

• Formation of germinal centres

• Provide help to B-cells for antibody production

• IL-21 release drives B-cell proliferation

What do Tfh cells protect against?

Any pathogen which requires an antibody response

Tfh cells are associated with what types of autoimmune diseases?

Autoimmune diseases characterised by dysregulated antibody production 

Th1, Th2, Th17, Th22, Th9, Treg and Tfh are all derived from what cell?

Naïve CD4 T-Cells

What three signals do Naive Th cells require to become activated?

• TCR binding to peptide-MHC II complex

  • Activation

• Co-stimulation by CD28 binding to CD80/86

  • Survival and clonal expansion

• Cytokines which act on the T-cell

  • Polarisation/Differentiation

What determines the differentiation of naïve T-cells?

The cytokines present during their activation determine their differentiation 

Presence of IL-12 and IFN-gamma causes naive T-cell differentiation into what?

Th1 cells

Presence of IL-4 causes naive T-cell differentiation into what?

Th2 cells

Presence of IL-6, IL-1beta and IL-23 causes naive T-cell differentiation into what?

Th17 cells

Cytokine receptors signal through which pathway?

JAK/STAT signalling pathway

How does the JAK/STAT signalling pathway work?

• Cytokine binds cytokine receptor

• Activates JAK which phosphorylates STAT

• Phosphorylated STAT molecules dimerise and move to nucleus

• Transcription of certain genes are then promoted

Different T helper subsets are defined by the presence of what?

A unique master transcription factor. 

All cytokine receptors use the same STAT molecules to influence gene transcription.

True or False.

False.

There are numerous STAT molecules (STAT1, STAT3, STAT5, etc)

These is involved with different cytokine receptors.

What is the master transcription factor of Th1 cells?

T-bet

What is the master transcription factor of Th2 cells?

GATA-3

What is the master transcription factor of Th17 cells?

ROR-yt

What is the master transcription factor of Treg cells?

FoxP3

What is the master transcription factor of Tfh cells?

Bcl-6

What are the roles of the master transcription factors?

• Dictate polarisation/differentiation of Th subsets

  • Induce specific Th subset genes

  • Repress genes specific to other Th subsets

How can Th17 cells be seen as ‘pathogenic’ and ‘non-pathogenic’?

Pathogenic

• Can promote inflammation

• Upregulate pro-inflammatory cells

• Secrete pro-inflammatory cytokines

Non-pathogenic

• Can downregulate inflammation

• Maintains homeostasis

• Secretes anti-inflammatory cells

Strength of TCR stimulation can affect T helper cell polarisation. What can alter the strength?

• Glycosylation

• Methylation

• Citrullination

Citrullination is catalysed by which enzyme?

PAD enzymes

• (Peptidylarginine deiminase) enzymes

Why are Anti-citrulline antibodies (ACPAs) a marker of aggressive arthritis? 

Citrullination is upregulated in apoptosis and inflammation

• Hence aggressive arthritis induces more citrullination and so more ACPAs

Citrullination enhances the production of which cytokine?

IL-17 production

• Pro-inflammatory cytokine