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
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