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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