IMMU3102 L15: T helper and Innate Lymphoid cells: Lineage

commitment and Effector Functions

Th cells differentiate into subsets to carry out different functions
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Thp + IL-12 Th1

Thp + IL-4 Th2
Th9
Thp + IL-23 Th17
Th22
Treg
TFH

MSMD
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Rare syndrome, characterized by a vulnerability to infection with

mycobacteria
associated with genetic defects in members of the IL-12 / IFN-
signalling pathway

Th1 and Th2

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Th1:
o Produce TNF
o Produce IFN-:
Activate macrophage control intracellular

parasite/bacteria
Immunity against mycobacteria in humans
Stimulate B cells produce antibodies mediate
opsonisation and subsequent phagocytosis of

extracellular infection
Th2:
o Produce IL-4, IL-5, IL-10 IL-13:
IL-4 stimulate B cells to produce antibodies (IgG4)
against Helminths, stimulate B cells to produce IgE to
trigger mast cell degranulation
IL-4, IL-13 alternative activation of macrophage
o INHIBITS macrophage activation (i.e. inhibit Th1 response)

Implications of Th1 and Th2

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Host has ability to generate particular type of effector T cell subset

determines outcome of infection

Cytokines produced by particular effector T cell subset mediate antimicrobial actions

Th1 allow resistance to intracellular bacterial and protozoan

infection
Th2 allow resistance to Helminth infection
o Th2 also causes allergy and asthma (via Mast cell stimulation)

Th17
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Effector functions immunity against extracellular bacteria and

fungi
Thus Th17 function is to activate Tissue cells via IL-17 to produce
inflammatory cytokines to attract neutrophils
o Important in mucosal immunity

Factors that regulate Th cell differentiation and Function

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Recognition of pathogens by innate cells provide signals for CD4+ T

cells effector choice

Development of Th1 cells

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Involves IL-12 and T-bet (a master regulator, transcription factor):

o IFN- produced by innate cells trigger T-bet within Th cells to

produce more IFN- which then act in an autocrine fashion

amplify signal
o IL-12 and IFN- then allow Th to differentiate into Th1
Th1 effector functions:
o Macrophage activation
o Production of antibodies via B cell stimulation

Development of Th2 cells

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Involves IL-4 and GATA3 (transcription factor):

o IL-4 produced by innate cells trigger GATA-3 within Th cells to
produce more IFN- which then act in an autocrine fashion

amplify signal
o IL-4 allow Th to differentiate into Th2
TH2 effector functions:
o Produce IL-4 IgE production
o Produce IL-5 Eosinophil activation
o Produce Il-13 Mucosal secretions

Development of Th17 cells

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Involves TGF-, IL-1, IL6, IL-23 and RORT:

o TGF- produced by DC trigger RORT within Th cell to produce

o
Th17
o
o

IL-21
IL-21 act in an autocrine fashion
TGF-, IL6, IL-23 allow Th to differentiate into Th17
effector functions:
Produce IL-17 induce inflammation
Produce IL-22 barrier function

Th cell subsets and expression of cytokine/chemokine receptors

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Nave T cells express IL-4 (IL-4R+) receptors but NOT IL-12 receptors
(IL-12R-)
o Thus Nave T cells can differentiate directly into Th2 cells prior

to activation
Th1 cells express IL-12R but NOT IL-4

o Thus Nave T cells need to be activated first before they can

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differentiate into Th1 cell

Th1 cell express CXCR3 chemokine receptor
Th2 cell express CCR4
TH17 express CCR6

Cross-regulation of T cell subsets by cytokines

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Th1 IFN- inhibits Th2 proliferation

Th2 IL-4, IL-10 inhibits Th1 proliferation
Th1 IL-12 inhibits Th17 proliferation
Th2 IL-4, IL-13 inhibits Th17 response
Th17 IL-17 inhibits Th1 proliferation

Summary of Factors that regulate Th cell differentiation and

functions
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Th lineage are regulated by and depend on:

o TCR strength (Th1 Strong, Th2 Weak)
o Transcription factors (Th1 T-bet, Th2 GATA3)
o Cytokines
Microbial components recognised by innate immunity trigger
production of cytokines (IL-12, IL-4, IL-1, IL-23) shape Th
differentiation process
o This is how immune response can respond to different

infections by generating different CD4 T cells

Cytokines produced by Th subset help promote expansion of that

subset over others

Chemokines direct Th cell migration in infection and inflammation

How immune system control infection: CD4+ Th cell effector

choice in infection
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Th cells are able to differentiate into Th cell subsets that fight

against different microbes:
o Th1 Intracellular bacteria and protozoa
o Th2 Helminths
o Th17 Extracellular bacteria and fungi

Plasticity of Th cell subsets

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IFN-, , cause Th2 cell to reprogram and become GATA-3+ and

T-bet+ cell subset I.e. new cell have both Th1 and Th2 features
Thus Th subsets are interconvertible

Plasticity of CD4 challenge classical T cell lineage differentiation

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Th subsets are interconvertible able to interconvert between

subsets

Summary of CD4+ Th cell functions and Th cell subsets

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CD4 Th cells are important in host defence and autoimmune

diseases as Th cells can differentiate into Th cell subsets to produce

different effector cytokines

CD4+ Th cells are tailored to combat different microbial pathogens

by differentiating into various subsets

Some CD4 T cell subsets are plastic and flexible able to
interconvert between one another

New source of Th cytokines: Innate Lymphoid Cells (ILCs)

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ILCs originate from lymphoid organs but lack recombined antigen

receptors
ILCs produce cytokines similar to those produced by Th cells
ILCs share common transcriptional program express

transcriptional regulator Id2 (inhibitor DNA binding 2)

Most ILCs express IL-7 receptor alpha (IL-7R) chain and require IL-

7R signalling for differentiation

ILCs highly populate mucosal surfaces
ILC functions:
o Epithelial homeostasis
o Mucosal defence
o Lymphoid tissue generation
o Tissue inflammation/remodelling/repair

ILCs are grouped into subsets based on cytokines they produce:

o ILC1s similar to Th1 produce IFN-
o ILC2s similar to Th2 produce IL-4, 5, 13
o ILC3s Similar to Th17 produce IL-17, IL-22
Cytokines produced by ILCs are similar to cytokines produced by Th

cell subsets
NK cells is a MEMBER of ILC