Navin K Verma nkvermantuedusg Tcell migration into inflamed tissues N Engl J Med 1999 341181728 Tcell migration in health and diseases Uncontrolled Tcell trafficking Chronic inflammatory diseases ID: 493139
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Slide1
LFA-1/ICAM-1 ligation in T-cells influences both Notch and TGF-β pathways
Navin
K.
Verma
nkverma@ntu.edu.sgSlide2
T-cell migration into inflamed tissues
N
Engl
J Med
1999; 341:1817-28.Slide3
T-cell migration in health and
diseases
Uncontrolled T-cell trafficking
Chronic inflammatory diseases
Regulated T-cell migration
Immune response regulationsSlide4
4
Resting
T-cells
Migrating
T-cells
Ong et al, 2014, J
Biol
Chem
;
Volkov
et
al,
2001,
Nat
Immunol
LFA-1
ICAM-1
Laboratory model of T-cell migration
Receptor activationSlide5
LFA-1/ICAM-1: changes in gene expression
TGF-
β
pathway
Notch pathway
Verma
et al.
(2012) J Biol ChemSlide6
LFA-1/ICAM-1 up-regulates both TGF-
β
inhibitory molecules and Notch signalling proteins
(verified by RT-qPCR
)TGF-β pathway
Notch pathway
Verma
et al. (2012) J Biol ChemSlide7
Notch Pathway:
LFA-1/ICAM-1
activates
Notch signalling
Unpublished data
pCBF1-Luc reporter
123Slide8
LFA-1/ICAM-1 activates
Notch signalling
NICD
Hey1
Hes1
α
-Tubulin
Time on ICAM-1 (h) 0 1 3 6 12
Unpublished data
3Slide9
LFA-1 regulates Notch via Akt/ERK/GSK3β signalling axisSlide10
10
LFA-1/ICAM-1
favors Notch-dependent
Th1 polarization
Unpublished dataSlide11
Notch Pathway summarySlide12
TGF-
β
pathway:
LFA-1/ICAM-1 up-regulates TGF-
β inhibitory molecules
Verma
et al.
(2012) J Biol ChemSlide13
LFA-1/ICAM-1-induced TGF-
β
inhibitory
pathway is dependent on STAT3 and/or JNK
Verma
et al.
(
2012) J Biol ChemSlide14
LFA-1 stimulated T-cells are refractory to
iTreg
or Th17 differentiation
iTreg
Th17
Human
Human
Human
Mouse
Mouse
Verma
et al.
(
2012)
J
Biol
ChemSlide15
Unpublished illustration
SMAD2
SMAD3
SMAD2
SMAD3
P
P
SMAD2
SMAD3
P
P
SMAD4
LFA-1
TGF-
β
TGF-
β
receptor
Inhibition of IL-2 secretion,
Th17,
iTreg
STAT3
STAT3
P
P
JNK
P
ICAM-1
SMAD7
SMURF2
SKI
SMAD2
SMAD3
P
P
SMAD4
SMURF2
SKI
SMAD7
STAT3
STAT3
P
P
c-Jun
c-Fos
AP-1
P
P
LFA-1/ICAM-1 signalling TGF-
β
signalling
Summary:
LFA-1/ICAM-1 induced TGF-
β
refractoriness in T-cellsSlide16
Funding support
Laboratory members
Navin
Fazil
Seow
C
arey
MadhaviJianhuiGraceAmuthaPraseetha
Existing collaborations
New collaborations