Programmed Death-1 (PD-1) in SLE T cells:
“That which does not kill us,
makes us stronger”
Maida Wong. M.D.
Assistant Clinical Professor
Division of Rheumatology
UCLA David Geffen School of Medicine
Systemic Lupus Erythematosus
Fate of a T cell
Block activation
Partially activated APC
Costimulation +/Naïve T cell
Suppression
Fully activated APC
Costimulation +++
Normal T cell
response
Deletion
Von Herrath MG et al. Nature Imunology 2003
Why are Tregs important?
Stimulating self-Ag:
Tolerance
Immunological tolerance: Unresponsiveness to an Ag by
exposing lymphocytes to that Ag (tolerogen)
• Breakdown of self-tolerance results in autoimmunity
Von Herrath MG et al. Nature Imunology 2003
Why does it matter?
Therapeutic potential
 Restore immune tolerance
 Treat autoimmune & allergic
diseases
 Prevent graft rejection
PD-1 controls dysregulated T cell activation
Normal T cell activation
Bc-xL
IL-2
IFN-ϒ
activated T cells
PD-1 controls dysregulated T cell activation
Normal T cell activation
Bc-xL
IL-2
IFN-ϒ
activated T cells
Anergy
PD-1
Bc-xL
IL-2
IFN-ϒ
Functional unresponsiveness
PD-1 controls dysregulated T cell activation
Normal T cell activation
Bc-xL
IL-2
IFN-ϒ
activated T cells
Anergy
PD-1
Bc-xL
IL-2
IFN-ϒ
Functional unresponsiveness
glucose metabolism
protein synthesis
proliferation
cell survival
PD-1 controls dysregulated T cell activation
Normal T cell activation
Bc-xL
IL-2
IFN-ϒ
activated T cells
Anergy
PD-1
Bc-xL
IL-2
IFN-ϒ
Functional unresponsiveness
Abatacept (anti-CTLA-4)
glucose metabolism
protein synthesis
proliferation
cell survival
What happens to a T after PD-1 is activated?
+TGF-β
What happens to a T after PD-1 is activated?
+TGF-β
High PD-1:
 Cancer
 Infectious disease
Low PD-1:
 Autoimmunity
 Allergy
 Transplant rejection
Okazaki, T et al. Int. Immunol. 2007
Anti-PD1 drugs
FDA approved
Nivolumab (Opdivo)
Pembrolizumab (Keytruda)
In the pipeline
Pidilizumab
REGN2810
MDX1106-02
Anti-PD1 drugs
FDA approved
Nivolumab (Opdivo): melanoma, NSCL
Pembrolizumab (Keytruda): melanoma, NSCL
glioma, SCC (H&N)
In the pipeline
Pidilizumab: diffuse intrinsic pontine glioma, GBM
REGN2810
MDX1106-02: Hepatitis C
What cells are we targeting with PD-1 & its ligand?
Francisco LM, Sharpe A et al, Immunological Reviews, 2010.
What cells are we targeting with PD-1 & its ligand?
Francisco LM, Sharpe A et al, Immunological Reviews, 2010.
What cells are we targeting with PD-1 & its ligand?
Francisco LM, Sharpe A et al, Immunological Reviews, 2010.
What cells are we targeting with PD-1 & its ligand?
Francisco LM, Sharpe A et al, Immunological Reviews, 2010.
PD-1 & SLE
Background: PD1/PDL1 plays a role in lupus-like
autoimmunity
1. Normal mouse (B6) KO PD1 Nishimura H et al, Immunity, 1999
Glomerulonephritis
Inflammatory arthritis
IgG
C3
2. Lupus mouse (BXSB) with increased PDL1 expression
Ding H et al; Clin Immun 2006
• Protects from lupus nephritis
o  Hypercellularity & IgG deposition in glomeruli
o Inhibited IgG production
o Delay onset of proteinuria & anti-dsDNA
PD-1 and T cells in SLE
Hahn Lab
Lupus mouse (BWF1) tolerized with pCons (suppresses SLE):
• CD8+PD1+ cells
•  mRNA of PD1 in CD8+ cells
Singh RP, Hahn BH et al. JImmunol 2007
Hypothesis
• Regulation of signaling through
PD-1 controls Tregs and
autoimmunity in BWF1 lupus mice.
Hypothesis
• Regulation of signaling through
PD-1 controls Tregs and
autoimmunity in BWF1 lupus mice.
Disease-free
No SLE
SLE
SLE
[PD-1]
Experiment to examine PD-1 in Tregs
In vivo
anti-PD1 mAb 100 g IP qod x3
splenocytes
PBMC
10 wk old BWF1
• Apoptosis
• Flow cytometry
• ELISA
• Microarray
• Clinical data
Clinical Results in Mouse SLE
survival
100
100
75
75
% survival
% proteinuria >2+
proteinuria
50
25
50
25
0
0
30
32
34
36
Age (weeks)
38
35
40
37
39
41
43
45
Age (weeks)
47
49
IgG isotype
pCons + anti-PD-1
anti-dsDNA
ELISA index
100
IgG isotype
75
50
25
0
15
20
25 30 35
Age (weeks)
40
Clinical Results in Mouse SLE
survival
100
100
75
75
% survival
% proteinuria >2+
proteinuria
50
25
50
25
0
0
30
32
34
36
Age (weeks)
38
35
40
37
39
41
43
45
Age (weeks)
47
49
IgG isotype
pCons
pCons + anti-PD-1
anti-dsDNA
ELISA index
100
IgG isotype
75
pCons
50
25
0
15
20
25 30 35
Age (weeks)
40
Wong M, Hahn BH et al. JImmunol 2011
Clinical Results in Mouse SLE
survival
100
100
75
75
% survival
% proteinuria >2+
proteinuria
50
25
50
p <0.0001
 2=3.965
25
0
0
30
32
34
36
Age (weeks)
38
40
35
p <0.0001
(2-way ANOVA)
anti-dsDNA
ELISA index
100
37
39
41
43
45
Age (weeks)
47
49
IgG isotype
anti-PD-1
pCons
pCons + anti-PD-1
*
**
**
**
#
##
##
##
75
IgG isotype
anti-PD-1
pCons
pCons + anti-PD-1
50
25
0
15
20
25 30 35
Age (weeks)
40
Wong M, Hahn BH et al. JImmunol 2011
Clinical Results in Mouse SLE
survival
100
100
75
75
% survival
% proteinuria >2+
proteinuria
50
25
50
p <0.0001
 2=3.965
25
0
0
30
32
34
36
Age (weeks)
38
40
35
p <0.0001
(2-way ANOVA)
• Anti-PD-1 delays nephritis and prolongs survival.
anti-dsDNA
ELISA index
100
*
**
**
**
#
##
##
##
75
37
39
41
43
45
Age (weeks)
47
49
IgG isotype
anti-PD-1
pCons
pCons + anti-PD-1
IgG isotype
anti-PD-1
pCons
pCons + anti-PD-1
50
25
0
15
20
25 30 35
Age (weeks)
40
• PD-1 blockade results in suppression of autoantibody production.
Wong M, Hahn BH et al. JImmunol 2011
Clinical Results in Mouse SLE
survival
100
100
75
75
% survival
% proteinuria >2+
proteinuria
50
25
50
p <0.0001
 2=3.965
25
0
0
30
32
34
36
Age (weeks)
38
40
35
p <0.0001
(2-way ANOVA)
• Anti-PD-1 delays nephritis and prolongs survival.
anti-dsDNA
ELISA index
100
*
**
**
**
#
##
##
##
75
37
39
41
43
45
Age (weeks)
47
49
IgG isotype
anti-PD-1
pCons
pCons + anti-PD-1
IgG isotype
anti-PD-1
pCons
pCons + anti-PD-1
50
25
0
15
20
25 30 35
Age (weeks)
40
• PD-1 blockade results in suppression of autoantibody production.
• Anti-PD1 added to pCons abrogates immune tolerance.
Wong M, Hahn BH et al. JImmunol 2011
Does the timing of PD-1 blockade matter?
75
75
% survival
100
% mice with proteinuria >2+
100
50
25
IgG isotype
anti-PD-1 (early)
anti-PD-1 (late)
50
25
0
30
32
34
36
Age (weeks)
38
40
0
35
37
39
41 43 45
Age (weeks)
47
49
Wong M, Hahn BH et al. JImmunol 2011
Does the timing of PD-1 blockade matter?
75
75
% survival
100
% mice with proteinuria >2+
100
50
25
IgG isotype
anti-PD-1 (early)
anti-PD-1 (late)
50
25
0
30
32
34
36
Age (weeks)
38
40
0
35
37
39
41 43 45
Age (weeks)
47
49
Wong M, Hahn BH et al. JImmunol 2011
Does the timing of PD-1 blockade matter?
75
75
% survival
100
% mice with proteinuria >2+
100
50
25
IgG isotype
anti-PD-1 (early)
anti-PD-1 (late)
50
25
0
30
32
34
36
Age (weeks)
38
40
0
35
37
39
41 43 45
Age (weeks)
47
49
• Later in disease, PD-1 blockade can delay disease progression, but
the effect is diminished.
Wong M, Hahn BH et al. JImmunol 2011
PD1
What is PD-1 blockade actually doing in Tregs?
PD1hi
PD1lo
49
30 PD1hi
16
33 PD1lo
CD4+CD25+
IgG isotype in vivo
anti-PD1 in vivo
Wong M, Hahn BH et al. JImmunol 2013
15
%CD4 CD25 PD1 cells
4
hi
+
%CD4 CD25 Foxp3 cells
PD-1 blockade in Tregs increases Foxp3 expression
3
+
+
10
+
+
2
1
0
10
15
20
Age (weeks)
25
30
IgG isotype
5
0
10
15
20
Age (weeks)
25
30
BWF1, IgG isotype
Wong M, Hahn BH et al. JImmunol 2013
** *
15
%CD4 CD25 PD1 cells
4
*
*
25
30
hi
+
%CD4 CD25 Foxp3 cells
PD-1 blockade in Tregs increases Foxp3 expression
3
+
+
10
+
+
2
1
0
10
15
20
Age (weeks)
25
30
IgG isotype
anti-PD1
5
0
10
15
20
Age (weeks)
BWF1, IgG isotype
BWF1, anti-PD1
* p < 0.05
** p < 0.01
Wong M, Hahn BH et al. JImmunol 2013
Experiment to examine PD-1 in Tregs
In vitro
10 wk old BWF1
Treg +/- anti-PD1
Splenocytes
for Treg, Th & B cells
Th
B
• Apoptosis
• Flow cytometry
•Functional assays
• ELISA
In vitro blockade of PD-1 expression in Tregs
CD4+Treg from IgG isotype control mice:
PD1
without anti-PD1
PD1hi
64
PD1lo
17
[anti-PD1] 75 mg/mL in vitro
19
44
PD1hi
PD1lo
CD4+CD25+
Wong M, Hahn BH et al. JImmunol 2013
40
%7AAD AnnexV CD19 cells
-
75
30
25
20
15
10
5
0
0
25
50
75
[anti-PD1] (g/ml)
100
+
+
35
50
-
+
+
+
%7AAD AnnexV CD4 CD25 cells
Does the degree of PD-1 blockade matter?
25
0
0
25
50
75
100
[anti-PD1] (g/ml)
Wong M, Hahn BH et al. JImmunol 2013
40
%7AAD AnnexV CD19 cells
-
75
30
25
20
15
10
5
0
0
25
50
75
[anti-PD1] (g/ml)
100
+
+
35
50
-
+
+
+
%7AAD AnnexV CD4 CD25 cells
Does the degree of PD-1 blockade matter?
25
0
0
25
50
75
100
[anti-PD1] (g/ml)
Wong M, Hahn BH et al. JImmunol 2013
**
*
40
%7AAD AnnexV CD19 cells
-
*
*
0
25
75
30
25
20
15
10
5
0
0
25
50
75
[anti-PD1] (g/ml)
100
+
+
35
50
-
+
+
+
%7AAD AnnexV CD4 CD25 cells
Does the degree of PD-1 blockade matter?
25
0
50
75
100
[anti-PD1] (g/ml)
* p < 0.05
** p < 0.01
Wong M, Hahn BH et al. JImmunol 2013
**
*
40
%7AAD AnnexV CD19 cells
-
*
*
0
25
75
30
25
20
15
10
5
0
0
25
50
75
[anti-PD1] (g/ml)
100
+
+
35
50
-
+
+
+
%7AAD AnnexV CD4 CD25 cells
Does the degree of PD-1 blockade matter?
25
0
50
75
100
[anti-PD1] (g/ml)
* p < 0.05
** p < 0.01
Wong M, Hahn BH et al. JImmunol 2013
**
*
40
%7AAD AnnexV CD19 cells
-
*
*
0
25
75
30
25
20
15
10
5
0
0
25
50
75
[anti-PD1] (g/ml)
100
+
+
35
50
-
+
+
+
%7AAD AnnexV CD4 CD25 cells
Does the degree of PD-1 blockade matter?
25
0
50
75
100
[anti-PD1] (g/ml)
* p < 0.05
** p < 0.01
• The amount of PD-1 expression has to be finely tuned – neither
absent nor high – for effective suppressive function in Tregs.
Wong M, Hahn BH et al. JImmunol 2013
1. Attenuated PD-1 expression makes Treg more
effective as suppressor cells:
 survival:
 survival:
• Treg
• Th
• B
Wong M, Hahn BH et al. JImmunol 2013
1. Attenuated PD-1 expression makes Treg more
effective as suppressor cells:
 survival:
 survival:
• Treg
• Th
• B
2. Attenuated PD-1 expression alters cytokine
production of Tregs that controls inflammation:
 production:
• TGF-β
• IL-2
 production:
•
•
•
•
•
anti-dsDNA
IgG
IFN-γ
IL-6
IL-10
Wong M, Hahn BH et al. JImmunol 2013
Genes influenced by PD-1 that alters Treg fitness
Gene
Fold up- or
down regulation
7.54
7.16
4.47
-3.59
-4.2
-4.94
-5.89
-9.09
-10.41
-23.12
-23.97
t-test
p-value
0.018
0.002
0.002
0.012
0.028
0.001
0.015
0.06
0.0001
0.027
0.034
Prdx2
Bcl2
Birc5
Traf2
Tnfsf10
Card6
Up-/downregulation (fold)
4.47
3.84
3.36
-3.24
-3.61
-3.67
t-test
p-value
0.002
0.002
0.05
0.06
0.01
0.002
Casp8
Tbfrsf10b
Traf3
Pycard
Traf1
Fasl
Cd40lg
-5.43
-6.35
-6.41
-6.58
-6.6
-7.39
-18.71
0.002
0.002
0.002
0.002
0.002
0.002
0.002
Tcf7
Bcl2l1
Birc5
Ccl2
Hk2
Brca1
Cd5
Cdkn1a
Tfrc
Fasl
Fn1
Gene
Zap70/Syk
NFAT
NFkB
Pro-apoptotic
anti-apoptotic
(TNFR)
Genes influenced by PD-1 that alters Treg fitness
Gene
Fold up- or
down regulation
7.54
7.16
4.47
-3.59
-4.2
-4.94
-5.89
-9.09
-10.41
-23.12
-23.97
t-test
p-value
0.018
0.002
0.002
0.012
0.028
0.001
0.015
0.06
0.0001
0.027
0.034
Prdx2
Bcl2
Birc5
Traf2
Tnfsf10
Card6
Up-/downregulation (fold)
4.47
3.84
3.36
-3.24
-3.61
-3.67
t-test
p-value
0.002
0.002
0.05
0.06
0.01
0.002
Casp8
Tbfrsf10b
Traf3
Pycard
Traf1
Fasl
Cd40lg
-5.43
-6.35
-6.41
-6.58
-6.6
-7.39
-18.71
0.002
0.002
0.002
0.002
0.002
0.002
0.002
Tcf7
Bcl2l1
Birc5
Ccl2
Hk2
Brca1
Cd5
Cdkn1a
Tfrc
Fasl
Fn1
Gene
Zap70/Syk
NFAT
NFkB
Pro-apoptotic
anti-apoptotic
(TNFR)
- OX40
Genes influenced by PD-1 that alters Treg fitness
Gene
Fold up- or
down regulation
7.54
7.16
4.47
-3.59
-4.2
-4.94
-5.89
-9.09
-10.41
-23.12
-23.97
t-test
p-value
0.018
0.002
0.002
0.012
0.028
0.001
0.015
0.06
0.0001
0.027
0.034
Prdx2
Bcl2
Birc5
Traf2
Tnfsf10
Card6
Up-/downregulation (fold)
4.47
3.84
3.36
-3.24
-3.61
-3.67
t-test
p-value
0.002
0.002
0.05
0.06
0.01
0.002
Casp8
Tbfrsf10b
Traf3
Pycard
Traf1
Fasl
Cd40lg
-5.43
-6.35
-6.41
-6.58
-6.6
-7.39
-18.71
0.002
0.002
0.002
0.002
0.002
0.002
0.002
Tcf7
Bcl2l1
Birc5
Ccl2
Hk2
Brca1
Cd5
Cdkn1a
Tfrc
Fasl
Fn1
Gene
Cell Cycle
Zap70/Syk
NFAT
NFkB
Pro-apoptotic
anti-apoptotic
(TNFR)
- OX40
Arrest: DNA damage
Anti-proliferative factors
UV
Lack of growth factors
High PD-1 signaling arrests cell cycle
progression to the G1 phase in Tregs
p = 0.05
50
150
%S phase
100
40
30
20
50
10
0
1
PD
D
P
ti
n
a
an
ti-
G
Ig
1
0
Ig
G
G1 arrest index
p =0.006
60
200
Summary
• Regulation of PD-1 appears critical to the generation and
maintenance of regulatory CD4+ T cells during immune
tolerance.
• Quantitative & timing of PD-1 expression to Ag has to be
finely tuned – neither absent nor high – to enable Tregs to
control autoimmunity.
• PD-1 blocks cell cycle progression and proliferation in
Tregs, possibly between the G1-S phase.
Human Data
Patient Demographics
n
Age (SD)
% Female
Ethnicity
Causasian
Black
Asian
Hispanic
SLEDAI
Patient
60
45.2 (15.7)
91.7
Control
30
43.1 (13.5)
93.3
0.52
0.07
0.17
0.25
10.8 (4.4)
0.67
0.07
0.20
0.07
0
%CD4+CD25hi Foxp3+ cells
Higher intensity of PD-1 expression in Tregs of
PBMC from SLE patients
7.5
p = 0.02
5.0
2.5
0.0
Healthy ctrls
SLE pts
7.5
p = 0.02
+
5.0
%CD4 CD25 Foxp3 cells being PD1
50
40
30
20
hi
2.5
p < 0.002
10
+
%CD4+CD25hi Foxp3+ cells
+
Higher intensity of PD-1 expression in Tregs of
PBMC from SLE patients
0.0
Healthy ctrls
SLE pts
0
Healthy ctrls
SLE pts
+
5.0
50
40
30
20
Healthy ctrls
SLE pts
+
50
40
30
20
10
+
10
+
0.0
p = 0.07
hi
hi
2.5
p < 0.002
+
p = 0.02
%CD4 CD25 Foxp3 cells being PD1
7.5
%CD4 CD25 Foxp3 cells being PD1
%CD4+CD25hi Foxp3+ cells
+
Higher intensity of PD-1 expression in Tregs of
PBMC from SLE patients
0
Healthy ctrls
SLE pts
0
SLEDAI <4
SLEDAI >4
+
5.0
50
40
30
20
Healthy ctrls
SLE pts
+
50
40
30
20
10
+
10
+
0.0
p = 0.07
hi
hi
2.5
p < 0.002
+
p = 0.02
%CD4 CD25 Foxp3 cells being PD1
7.5
%CD4 CD25 Foxp3 cells being PD1
%CD4+CD25hi Foxp3+ cells
+
Higher intensity of PD-1 expression in Tregs of
PBMC from SLE patients
0
Healthy ctrls
SLE pts
0
SLEDAI <4
SLEDAI >4
• SLE patients have increased PD-1 expression in Tregs compared
to healthy individuals & patients with mild disease.
Wong M, Hahn BH et al. Arthritis Rheum 2014. (Abstract)
Clinical symptoms associated with increased PD-1
Clinical manifestation
%PD1hiCD4+CD25+ cells
no symptoms
p-value
with symptoms
Vasculitis
7.93 ± 1.59
15.54 ± 3.94
0.029
Renal
10.48± 5.26
21.45 ± 9.18
0.052
Thrombocytopenia (plt < 1K)
6.64 ± 1.03
11.55 ± 3.46
0.036
Leukopenia (WBC < 3.5)
6.61 ± 1.41
11.30 ± 2.69
0.014
Oral/Nasal ulcers
8.84 ± 1.47
11.19 ± 5.61
0.023
Rash (acute, subacute, discoid)
10.02 ± 1.93
6.79 ± 1.60
0.014
9.95 ± 1.68
3.52 ± 1.07
0.013
Photosensitivity
Wong M, Hahn BH et al. Arthritis Rheum 2014. (Abstract)
p <0.05 (1-way ANOVA)
25
20
+
hi
%AnnexinV 7AAD CD4 CD25 cells
Low PD-1 expression induced suppressivity in
Treg of SLE patients
*
*
10
20
-
15
+
10
5
0
0
2.5
[anti-PD1] (g/ml)
20
*
*
-
15
+
10
5
0
0
2.5
10
20
[anti-PD1] (g/ml)
%AnnexinV+7AAD-CD19+ cells
p <0.05 (1-way ANOVA)
25
+
hi
%AnnexinV 7AAD CD4 CD25 cells
Low PD-1 expression induced suppressivity in
Treg of SLE patients
p < 0.05
60
40
20
0
0
10
[anti-PD1] to treat CD4+ Treg (g/ml)
*
*
-
15
+
10
5
0
0
2.5
10
20
[anti-PD1] (g/ml)
p < 0.05
60
40
20
0
0
10
CD4+CD25- Th cell division index
20
%AnnexinV+7AAD-CD19+ cells
p <0.05 (1-way ANOVA)
25
+
hi
%AnnexinV 7AAD CD4 CD25 cells
Low PD-1 expression induced suppressivity in
Treg of SLE patients
p <0.005
2.0
1.5
1.0
0.5
0.0
0
10
[anti-PD1] to treat CD4+ Treg (g/ml) [anti-PD1] to treat CD4+ Treg (g/ml)
n = 11
*
*
-
15
+
10
5
0
0
2.5
10
20
[anti-PD1] (g/ml)
p < 0.05
60
40
20
0
0
10
CD4+CD25- Th cell division index
20
%AnnexinV+7AAD-CD19+ cells
p <0.05 (1-way ANOVA)
25
+
hi
%AnnexinV 7AAD CD4 CD25 cells
Low PD-1 expression induced suppressivity in
Treg of SLE patients
p <0.005
2.0
1.5
1.0
0.5
0.0
0
10
[anti-PD1] to treat CD4+ Treg (g/ml) [anti-PD1] to treat CD4+ Treg (g/ml)
n = 11
• Tolerance can be induced in Treg by PD-1 blockade at a finetuned concentration.
Wong M, Hahn BH et al. Arthritis Rheum 2014. (Abstract)
Attenuated PD-1 expression makes Treg more
effective as suppressor cells:
 survival:
 survival:
• Treg
• Th
• B
Attenuated PD-1 expression alters cytokine
production of Treg that controls inflammation:
 production:
• TGF-β
• IL-2
 production:
•
•
•
•
•
anti-dsDNA
IgG
IFN-γ
IL-6
IL-17
Attenuated PD-1 expression makes Treg more
effective as suppressor cells:
 survival:
 survival:
• Treg
• Th
• B
Attenuated PD-1 expression alters cytokine
production of Treg that controls inflammation:
 production:
• TGF-β
• IL-2
 production:
•
•
•
•
•
anti-dsDNA
IgG
IFN-γ
IL-6
IL-17
Reprise of
lupus mouse
data
Future Directions
Mouse
• Bone marrow chimeric model
• PD-1 on/off switch
Human
• PDL1 expression on target cells
• TNFR: OX40
• Renal disease
• Clinical application
Summary
• SLE patients have aberrant, increased PD-1
expression in their circulating Tregs that may
reduce the regulatory function of Foxp3+ Tregs,
which are important in the suppression of
autoimmunity.
• One mechanism by which PD-1 sustains these
Tregs is by reducing their susceptibility to
apoptosis.
Conclusion
 PD-1 influences autoimmunity in part via
its effect on Tregs.
 PD-1 expression in Tregs must be tightly
controlled in a graded fashion to maintain
their numbers and suppressive functions.
 PD-1 has the potential to be a target for
treatment of SLE.
Acknowledgements
 Bevra Hahn





 George Tsokos
Betty Tsao
Antonio La Cava
Daniel Furst
Jennifer Grossman
Elaine Lourenço
Grant support
 NIH (T32)
 Arthritis Foundation (Local & National Chapter)
 American College of Rheumatology
 Arthritis National Research Foundation
Revival of “Exhausted” T cells
Acute infection
Chronic infection
Revival of exhausted cells
Williams MA et al. Nature Immunology, 2006.