Targeting metabolism in immune cells: a better way to ... · Targeting metabolism in immune cells:...
28
Targeting metabolism in immune cells: a better way to immunodulation [email protected] São Paulo 2016 Niels Olsen Saraiva Câmara FAPESP/EU-LIFE Symposium on Cancer Genomics, Inflammation & Immunity
Transcript of Targeting metabolism in immune cells: a better way to ... · Targeting metabolism in immune cells:...
-
Targeting metabolism in immune cells:
a better way to immunodulation
São Paulo2016
Niels Olsen Saraiva Câmara
FAPESP/EU-LIFE Symposium on Cancer Genomics, Inflammation & Immunity
mailto:[email protected]
-
SELZNER ET AL
`Conventional` immunosuppression
-
Immunosuppression in Transplantation
-
BC TransplantHariharan et al.
Outcomes in Transplantation
1st-yr 10th-yr
-
Halloran, P et al.
Usual targets in classical immunosuppression
-
Common targets
Nankivell & Alexander
-
Wang & Green
Sources of energy for expansion and differentiation of T cells
-
Metabolic alterations during T cell activation
Pea
rce
eta
l.,
20
13,
Sci
ence
-
Finlay D, 2013 Biochem Soc Trans
naive activated
Metabolic alterations during T cell activation
-
Po
wel
l et
al.
Sensors of metabolic alterations
-
Powell et al.
mTOR complexes
-
Metabolism of T helper cells
-
mTORC1-/-
T cells
B6
Balb/c
Skin Tx
7th day post-tx
Normal T cells mTORC1-/- T cells
Absence of mTORC1 in T cells protects against fully mismatched graft
Nor
mal
T c
ell
mTO
RC1-
/- T
cells
0.0
0.5
1.0
1.5
2.0
2.5 p
-
mTORC2-/-
T cells
B6
Balb/c
Skin Tx Normal T cells mTORC2/- T cells
7th day post-tx
Absence of mTORC2 in T cells has not effect on fully mismatched graft
-
The role of Rheb (mTORC1 deficient) in Th1 and Th2 cells
Delgoffe et al., 2011 Nat ImmPowell et al., 2013 CSHSQB
-
Hardie DG, et al.
AMPK
-
AMPK-/-
T cells
B6Balb/c
Skin TxNormal T cells AMPK-/- T cells
7th day post-tx
Absence of AMPK in T cells protects against fully mismatched graft
-
2-DG Combined with Metformin Inhibits T Cell Responses through Suppression of Glycolysis
Vinicius Andadre-Oliveira
-
Combined Inhibition of Glycolysis and Glutaminolysis Profoundly Suppresses T Cell Responses
Vinicius Andadre-Oliveira
-
Skin
Inhibition of metabolic pathways prolongs graft srurvival
Heart
Vinicius Andadre-Oliveira
-
Vinicius Andadre-Oliveira
-
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
1
2
3
4
Raptorfl/fl
CD4cre-
Raptorfl/fl
CD4cre+
Days after immunization
Clin
ical S
co
re E
AE
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
1
2
3
4
Raptorfl/fl
CD4cre-
Raptorfl/fl
CD4cre+
Days after immunization
Clin
ical S
co
re E
AE
Absence of mTORC1 but not mTORC2 inT cells protects from EAE
0 1 2 3 4 5 6 7 8 9 1011121314151617180
1
2
3
4
Rictorfl/fl
CD4cre-
Rictorfl/fl
CD4cre+
Days after immunization
Clin
ical S
co
re E
AE
0 1 2 3 4 5 6 7 8 9 1011121314151617180
1
2
3
4
Rictorfl/fl
CD4cre-
Rictorfl/fl
CD4cre+
Days after immunization
Clin
ical S
co
re E
AE
-
Deficiency in mTORC1 in T cells impairs T cell response
0
1000
2000
3000
4000
Raptorfl/fl
CD4cre-
Raptorfl/fl
CD4cre+
MOG35-55 -10
g/mL
100
g/mL
*
*
IFN
- (
pg
/mL
)
0
200
400
600
800
*
MOG35-55 -10
g/mL
100
g/mL
IL-1
7A
(p
g/m
L)
0
10
20
30
40
50
*
*
MOG35-55 -10
g/mL
100
g/mL
IL-2
(p
g/m
L)
0
5
10
15
20
** Raptorfl/fl CD4cre-
Raptorfl/fl
CD4cre+
% C
D4
+IF
N
+
0
5
10
15
20
**Raptor
fl/fl CD4
cre-
Raptorfl/fl
CD4cre+
% C
D4
+ I
L-1
7A
+
-
0 1 2 3 4 5 6 7 8 9 1011121314151617180
1
2
3
4
AMPKfl/fl
CD4cre-
AMPKfl/fl
CD4cre+
Days after immunization
Clin
ical S
co
re E
AE
0 1 2 3 4 5 6 7 8 9 1011121314151617180
1
2
3
4
AMPKfl/fl
CD4cre-
AMPKfl/fl
CD4cre+
Days after immunization
Clin
ical S
co
re E
AE
Absence of AMPK in T cells protects from EAE
-
AMPK is important to induce aerobic glycolysis upon TCR activation
0
10
20
30
40
50
CD3+CD28: - - + +
* CD4Cre- ampkfl/fl
CD4Cre+ ampk
fl/fl
Lacta
te (
mg/d
L)
0
10
20
30
40
50
CD3+CD28: - - + +
* CD4Cre- ampkfl/fl
CD4Cre+ ampk
fl/fl
Lacta
te (
mg
/dL
)
0
50
100
150
200
CD3+CD28: - - + +
OC
R (
pm
ole
s/m
in)
0
2
4
6
8
10
*
CD3+CD28: - - + +
EC
AR
(m
pH
/min
)
Source: Searhorse, Illumina
-
AMPK Neg AMPK Cre
Th1
AMPK modulates Th1 differentiation
Metformin
-
Working hypothesis
Antigen Processing T cell expansionAntigen Presentation T cell differentiation
Energy requirements Metabolic sensors T cell differentiation
Bortezomib® Belatacept® Calcineurin Inhibitors
To be addressed…
-
Fernanda TerraAmanda CampeloAngela CastoldiFelipe ValençaMarina BurghosProfa. Alicia KowaltowskiLeandro AraujoProf. Alexandre Basso
Prof. Jonathan Powell, Johns Hopkins
