CD4 T cells: fates, functions, and faults

15.02.2010

NaiveCD4 T

Th 1

Th 2

Th 17

iTreg

IL-4 GATA-3

IL-2

IFNγIL-12

IL-4

T-bet

A little history

15.02.2010

IL-23

•Not produce classical Th1/Th2 cytokines•Low levels GATA-3/T-bet•IL-4/IFNγ supress differentiation

IL-6

TGFβRORγt

+ IL-1IL-21

Foxp3 TGFβ

TGFβ

NaiveCD4 T

Th 1

Th 2

Th 17

iTreg

IL-4 GATA-3/Stat5

IL-2

IFNγIL-12

IL-4

IL-2

T-bet/Stat4

A little history

15.02.2010

IL-23IL-6

TGFβRORγt/Stat3

+ IL-1IL-21

Foxp3/Stat5 TGFβ

TGFβ

LTα

IFNγ

(IL-10)

IL-5

IL-13

IL-25IL-10

Amphiregulin

IL-10

IL-35

IL-17f

IL-17aIL-22

(IL-10)IL-21

+ IL-2

Extracellular bacteriaFungiAutoimmunity

Intracellular pathogensAutoimmunity

Immune toleranceLymphocyte homeostasisRegulation of immune responses

Extracellular pathogensAllergy and asthma

Factors of differentiation Produced cytokines Transcription factors

Cytokines

The cells: cytokine produced and functions

15.02.2010

Th 1

Intracellular pathogens (Mycobacteria)Autoimmunity

IFNγ

Activate macrophages to increase their microbicidal activity

LTα

IL-2

CD4 cell memory(critical for CD8 memory formation)

Mediates variety of inflammatory, immunostimulatory, and antiviral responses

Th 2

Extracellular pathogens (helmints)Allergy and asthma

Positive feedback for Th2 differentiation

NaiveCD4 T

IL-4

Major mediator for IgE in B cells

Basophil

Mast cell

FcЄRI FcЄRI

histamine

serotonin IL-4 IL-13TNF-α

IL-5

Recruits eosinophilsEosinophil

IL-9

Mast cell

lymphocyte

Recruits mast cells and lymphocytesInduces mucin production

Epithelial cell

mucin

IL-10Th 1

Supression of Th1

Dendritic cell

Supression of dendritic cells function

IL-13

Expulsion of helmintsAirway hypersensitivity

AmphiregulinEpithe

lial cell

Induces epithelial cells proliferation IL-25

IL-17BIL-4IL-5 CCL5 CCL11

Eosinophil

Enhances IL-4 and IL-5 productionRecruits eosinophils

Th 17

Extracellular bacteriaFungiAutoimmunity

IL-17a

IL-17f

LCR

IL-17A

Higher affinity

Induction of inflammatory cytokinesIL-6

Induction of chemokines

IL-8Inflammatory responses

Neutro

phil

Neutro

philRecruit and activate nuetrophils

IL-21

NaiveCD4 T

Positive feedback amplifierActs on CD8, B cells, NK andDendritic cells

CD8 T Dendritic cell

NK

B cell

IL-6/IL-23Stat 6

IL-22Mediates dermal inflammationPrtotects hepatocytes during acute liver inflammationMediates host defence against bacteria (Klebsiella pneumoniae and Citrobacter rodentium)

The cells: cytokine produced and functions

15.02.2010

Treg

Immune toleranceLymphocyte homeostasisRegulation of immune responses

The cells: cytokine produced and functions

15.02.2010

TGFβ

Mediates supression in some cases

IL-10

Prevention and cure of inflammatory bowel diseaseLimits the severity of EAE (experimental autoimmune encephalomyelitis)Stimulation of protective immunity during the pathogen persistence

Negative regulatory mechanism for limmiting immune responses to prevent host tissue damage

IL-35

Supressive activity

Receptors

Expression of cytokine and chemokine receptors by Th cells

15.02.2010

NaiveCD4 T

Th 1

Th 2

Th 17

iTreg

IL-12Rβ2TCR activation

IFNγIL-12

IL-12Rβ1

IL-18Rα

CXCR3 CCR5

IL-4αIL-4

IL-2Rα(CD25)

IL-33Rα(T1/ST2)

CCR3CCR4

CCR8

CRTh2

IL-2

IL-23R

IL-18Rα

IL-1R1

CCR6 CCR4

IL-2Rα(CD25)

IL-2CTLA-4

GITR

Folr4

CD103

Transcriptional Factors

Transcriptional factors critical for each T helper lineage

15.02.2010

NaiveCD4 T

Th 1

Th 2

Th 17

iTreg

Transcriptional factors critical for each T helper lineage

15.02.2010

T-bet

Th1 master regulator

Stat1IFNγ mediatedInduction of T-bet

Stat4

IL-12 signal transducerIndice IFNγ productionin activated CD4 cells

Stat4IL-12NF-κB inducer

IFNγRunx3

Transcriptional repressor during CD8development

Stat6

IL-4

Major signal trancducerduring IL-4 mediated Th2differentiation

GATA-3Th2 master regulator

Stat5a/Stat5b

Cytokine driven proliferation and cell survival

IL-2

c-MafEnhances IL-4 production

Gfi-1Modulates IL-2 signals

RORγtTh17 differentiation

RORα

Stat3Major signal trancducer forIL-21, IL-23, IL-21 IL-23

IL-6IL-21

Induction of IL-23R

IRF4RORγt expression

Foxp3Maintaines suppressive sctivity

TGFβ

Stat5Th2 differentiation

IL-2

Treg development

Foxp3 induction

T helper differentiation

T helper differentiation

15.02.2010

T helper differentiationTh1 cell differentiation

15.02.2010

NaiveCD4 T

Dendritic cell IL-12

NK IFNγStat1 T-bet

IFNγ

NaiveCD4 T

NaiveCD4 T

NaiveCD4 T

IL-12Rβ2

Selection

IL-12

NaiveCD4 T

Stat4

NaiveCD4 TIFNγ

IL-12Rβ2(sustains)

NaiveCD4 T

IL-12Rβ2IFNγ

IL-18Rα

Stat4IL-12

IL-12IL-18

Th 1

IL-12Rβ2

IL-12Rβ1

IL-18Rα

CXCR3 CCR5

IL-2 LTα

IFNγ (IL-10)

T-bet/Stat4

T helper differentiationTh2 cell differentiation

15.02.2010

NaiveCD4 T

IL-4 IL-2

NaiveCD4 T

Stat6

GATA-3

exogenous

NaiveCD4 T

GATA-3 NaiveCD4 T

IL-4

NaiveCD4 T

Stat6

GATA-3

Gfi-1Transcriptionalrepressor

NaiveCD4 T

GATA-3

NaiveCD4 T

GATA-3

NaiveCD4 T

GATA-3

selects

IL-4

Stat5

NaiveCD4 T

IL-2

Stat5

HSII HSIII

Th 2

IL-4α

IL-2Rα(CD25)

IL-33Rα(T1/ST2)

CCR3CCR4

CCR8

CRTh2

IL-4

IL-5

IL-13IL-25

IL-10

Amphiregulin

GATA-3

Va CsnIl4/Il13

NaiveCD4 T

T helper differentiationTh17 cell differentiation

15.02.2010

Cells of innate immuntiy

IL-6 NaiveCD4 T

TGFβ

NaiveCD4 T

IL-21 RORγt

IL-23

IL-6IL-23

IL-21NaiveCD4 T

IL-21 RORγt

IL-23

Stat3

Th 17

IL-23R

IL-18Rα

IL-1R1

CCR6 CCR4

IL-21IL-17f

IL-17a IL-22

(IL-10)

T helper differentiationTreg cell differentiation

15.02.2010

TGFβ

NaiveCD4 T

Smad3

NFAT

NaiveCD4 T

foxp3

Foxp3

IL-2

NaiveCD4 T

Stat5

IL-2

TGFβiTreg

IL-2Rα(CD25)

CTLA-4

GITR

Folr4

CD103

TGFβ

IL-10

IL-35

Cross-regulation of differentiation

Cross-regulation of T helper differentiation

15.02.2010

Levels of cross-regulation:

•By cytokines•Transcriptional regulation of critical factors•Cytokine transcription

Cross-regulation of T helper differentiation

15.02.2010

T-betGATA-3

Th1Th2Th17Treg

IL-4TGFβTGFβ

Foxp3

RORγtRORγt

IL-17

Stat5

Stat3

Stat4

IL-2

Runx3Gfi-1

IFNγ

Epigenetic changes in Th differentiation

Epigenetic changes in Th differentiation

15.02.2010

Epigenetic changes in Th differentiation

15.02.2010

Immunologic abnormalities

Immunologic abnormalities resulting from mutations or polymorphisms in the pathways of Th differentiation

15.02.2010

Immunologic abnormalities resulting from mutations or polymorphisms in the pathways of Th differentiation

15.02.2010

Stat3 Susceptibility to some bacterial infectionsInability to develop Th17Th 17

TregFoxp3 IPEX syndrome (immunodysregulation,

polyendocrinopathy, enteropathy, x-linked)Inability to develop Treg

IL2RA IPEX like syndrome

Th 2GATA-3 HDR syndrome (hypoparathyroidism,

sensorineural deafness, renal dyplasia)Differentiation into Th2 is diminished

Th 1 T-bet Asthma and airway hyperresponsiveness

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