Download IL-2

CD4 T cells: fates, functions, and faults
15.02.2010
•Not produce classical Th1/Th2 cytokines
•Low levels GATA-3/T-bet
•IL-4/IFNγ supress differentiation
Th 17
IL-21
Th 1
IL-12
TGFβ + IL-1
IFNγ
RORγt
T-bet
IL-6
IL-23
Foxp3
iTreg
TGFβ
A little history
15.02.2010
TGFβ
Naive
CD4 T
IL-4
GATA-3
IL-2
Th 2
IL-4
Extracellular bacteria
Fungi
Autoimmunity
IL-22
IL-17a
IL-17f
Th 17
Th 1
RORγt/Stat3
IL-21
Foxp3/Stat5
IL-35
TGFβ
LTα
IL-12
TGFβ + IL-1
IFNγ
(IL-10)
T-bet/Stat4
IL-6
IL-23
IL-10
IL-2
IFNγ
IL-21
(IL-10)
Intracellular pathogens
Autoimmunity
Naive
CD4 T
TGFβ + IL-2
IL-4
GATA-3/Stat5
IL-2
iTreg
Th 2
IL-13
IL-4
IL-5
Immune tolerance
Lymphocyte homeostasis
Regulation of immune responses
Extracellular pathogens
Allergy and asthma
IL-10
Amphiregulin
IL-25
A little history
15.02.2010
Factors of differentiation
Produced cytokines
Transcription factors
Cytokines
Intracellular pathogens (Mycobacteria)
Autoimmunity
IFNγ
Activate macrophages to increase their microbicidal activity
LTα
Mediates variety of inflammatory, immunostimulatory, and antiviral responses
IL-2
CD4 cell memory
(critical for CD8 memory formation)
The cells: cytokine produced and
functions
15.02.2010
Th 1
mucin
Eosin
ophil
Epithe
lial
cell
lymph
ocyte
serotonin IL-4 IL-13
Recruits eosinophils
IL-5
Expulsion of helmints
Airway hypersensitivity
Mast
cell
Recruits mast cells and
lymphocytes
Induces mucin production
IL-9
FcЄRI
Dend
ritic
cell
FcЄRI
Major mediator for
IgE in B cells
IL-10
Th 1
Mast
cell
Baso
phil
IL-13
Supression of Th1
IL-4
Supression of
dendritic cells
function
Positive feedback for
Th2 differentiation
Amphiregulin
Epithe
lial
cell
TNF-α
histamine
Th 2
Induces epithelial
cells proliferation
IL-4
IL-5
IL-25
Naive
CD4 T
IL-17B
Enhances IL-4 and IL-5 production
Recruits eosinophils
CCL5
CCL11
Eosin
ophil
Extracellular pathogens
(helmints)
Allergy and asthma
Induction of chemokines
Naive
CD4 T
Induction of inflammatory
cytokines
IL-6
IL-8
Inflammatory responses
Th 17
IL-17a
LCR
Higher affinity
IL-17A
IL-6/IL-23
Stat 6
Recruit and activate
nuetrophils
Neutro
phil
IL-17f
CD8 T
Dend
ritic
cell
IL-21
Positive feedback amplifier
Acts on CD8, B cells, NK and
Dendritic cells
IL-22
Mediates dermal inflammation
Prtotects hepatocytes during acute liver inflammation
Mediates host defence against bacteria
(Klebsiella pneumoniae and Citrobacter rodentium)
The cells: cytokine produced and
functions
15.02.2010
NK
B cell
Extracellular bacteria
Fungi
Autoimmunity
Immune tolerance
Lymphocyte homeostasis
Regulation of immune responses
IL-10
Negative regulatory mechanism for limmiting
immune responses to prevent host tissue damage
Mediates supression in some cases
TGFβ
Prevention and cure of inflammatory bowel disease
Limits the severity of EAE (experimental autoimmune encephalomyelitis)
Stimulation of protective immunity during the pathogen persistence
IL-35
Treg
The cells: cytokine produced and
functions
15.02.2010
Supressive activity
Receptors
IL-18Rα
IL-1R1
IL-12Rβ1
IL-23R
IL-18Rα
IL-12Rβ2
TCR activation
Th 17
Th 1
IL-12
CCR6
IFNγ
CCR4
CCR5
CXCR3
Naive
CD4 T
CTLA-4
IL-2Rα
(CD25)
IL-2Rα
(CD25)
IL-2
GITR
iTreg
IL-4α
IL-4
IL-33Rα
(T1/ST2)
IL-2
CD103
Th 2
Folr4
CRTh2
CCR3
Expression of cytokine and
chemokine receptors by Th cells
15.02.2010
CCR4
CCR8
Transcriptional Factors
Transcriptional factors critical
for each T helper lineage
15.02.2010
Th17 differentiation
Transcriptional
repressor during CD8
Runx3
development
RORγt
RORα
IRF4
Th 17
RORγt expression
Stat3
Major signal trancducer for
IL-21, IL-23, IL-21
Induction of IL-23R
IL-21
IFNγ mediated
Induction of T-bet
Stat1
IFNγ
NF-κB inducer
Th 1
Stat4
IL-6
IL-23
Stat4
IL-12
T-bet
Th1 master regulator
IL-12 signal transducer
Indice IFNγ production
in activated CD4 cells
Naive
CD4 T
TGFβ
Cytokine driven proliferation and cell survival
Maintaines suppressive sctivity
Foxp3
iTreg
IL-2
Stat5
Th2 differentiation
Treg development
Foxp3 induction
Transcriptional factors critical
for each T helper lineage
15.02.2010
IL-4
IL-2
Stat5a/Stat5b
Major signal trancducer Stat6
during IL-4 mediated Th2
differentiation
Th2 master regulator
Th 2
GATA-3
Gfi-1
c-Maf
Enhances
IL-4
production
Modulates IL-2 signals
T helper differentiation
T helper differentiation
15.02.2010
Naive
CD4 T
Dend
ritic
cell
Naive
CD4 T
IL-12
NK
Naive
CD4 T
Stat1
IFNγ
T-bet
Naive
CD4 T
Selection
IFNγ
IL-12
IL-12Rβ1
IL-18Rα
IL-12Rβ2
IL-2
Stat4
LTα
Th 1
IFNγ
Naive
CD4 T
(IL-10)
CXCR3
CCR5
IL-18Rα
T-bet/Stat4
Stat4
IL-18
IL-12
T helper differentiation
Th1 cell differentiation
15.02.2010
IL-12Rβ2
IL-12
Naive
CD4 T
IFNγ
IL-12Rβ2
IFNγ
Naive
CD4 T
IL-12Rβ2
(sustains)
IL-4 exogenous IL-2
Naive
CD4 T
Stat6
Stat6
Naive
CD4 T
Naive
CD4 T
GATA-3
Naive
CD4 T
GATA-3
selects
Gfi-1
Transcriptional
repressor
IL-4
IL-4
GATA-3
Naive
CD4 T
GATA-3
IL-2Rα
(CD25)
IL-4α
IL-25
IL-13
IL-4
Th 2
IL-5
CRTh2
IL-33Rα
(T1/ST2)
Amphiregulin
CCR4
T helper differentiation
Th2 cell differentiation
15.02.2010
CCR8
IL-2
Naive
CD4 T
GATA-3
Naive
CD4 T
Naive
CD4 T
Stat5
GATA-3
IL-10
CCR3
GATA-3
Naive
CD4 T
Stat5
Il4/Il13
Va
Csn
HSII HSIII
Naive
CD4 T
Cells of innate immuntiy
Naive
CD4 T
IL-6
IL-18Rα
IL-1R1
TGFβ
IL-23R
IL-17a
Naive
CD4 T
IL-21
CCR6
Stat3
IL-23
Naive
CD4 T
IL-21
IL-21
T helper differentiation
Th17 cell differentiation
15.02.2010
IL-21
(IL-10)
RORγt
IL-6
Th 17
IL-17f
IL-23
IL-22
RORγt
IL-23
CCR4
TGFβ
Smad3
Naive
CD4 T
NFAT
CTLA-4
foxp3
IL-2
Naive
CD4 T
Stat5
Naive
CD4 T
IL-2
T helper differentiation
Treg cell differentiation
15.02.2010
IL-10
GITR
iTreg
TGFβ
Foxp3
IL-2Rα
(CD25)
CD103
Folr4
TGFβ
IL-35
Cross-regulation of differentiation
Levels of cross-regulation:
•By cytokines
•Transcriptional regulation of critical factors
•Cytokine transcription
Cross-regulation of T helper
differentiation
15.02.2010
Treg
Th17
TGFβ
IL-17
TGFβ
Th2
IL-2
Th1
IL-4
Stat5
RORγt
RORγt
Foxp3
Stat3
Stat4
GATA-3
Gfi-1
Cross-regulation of T helper
differentiation
15.02.2010
IFNγ
T-bet
Runx3
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
Th 17
Treg
Stat3
Susceptibility to some bacterial infections
Inability to develop Th17
Foxp3
IPEX syndrome (immunodysregulation,
polyendocrinopathy, enteropathy, x-linked)
Inability to develop Treg
IL2RA
IPEX like syndrome
GATA-3
HDR syndrome (hypoparathyroidism,
sensorineural deafness, renal dyplasia)
Differentiation into Th2 is diminished
T-bet
Asthma and airway hyperresponsiveness
Th 2
Th 1
Immunologic abnormalities resulting from mutations or
polymorphisms in the pathways of Th differentiation
15.02.2010
Thank You