View
41
Download
0
Category
Tags:
Preview:
DESCRIPTION
NICD. CAPT Network African Led, Canadian Enabled. Dissecting T cell responsiveness to C- cytokines in HIV-infected subjects. Catherine Riou NICD/PHRU Johannesburg, South Africa. How different T cell subsets respond to cytokines? - PowerPoint PPT Presentation
Citation preview
Dissecting T cell responsiveness to C-cytokines in HIV-infected subjects
Catherine Riou
NICD/PHRU
Johannesburg, South Africa
CAPTNetworkAfrican Led,Canadian Enabled
NICD
Background
• Cytokines play a key role in the proliferation, differentiation, function and survival of T cells.
• HIV-specific cells are defective in their ability to proliferate and to produce cytokines.
Less is known about T cell responsiveness to cytokine in HIV + individuals.
How different T cell subsets respond to cytokines?
Is cytokine responsiveness impaired in HIV-infected individuals?
Do specific profiles of T cells associate with viral control?
AIMS
- Study the phosphorylation profiles of different T-cell subsets in response to exogenous c-cytokine engagement
IL-2 : T cell proliferation and activated induced cell death (AICD) IL-7 and IL-15 : maintenance of T cells (IL-15 favours the cell proliferation and IL-7 rather favours cell survival).
- Study the phosphorylation profiles of HIV- and CMV-specific CD8+ T cells in response to exogenous c- cytokine triggering.
Study Subjects
HIV- HIV+
Age (p=NS) Median (range) 35 (27-60) 35 (21-57)
CD4 count (p<0.0001) Median (range) 953 (324-2119) 388 (137-1289)
Viral Load Median (range) NA 27900 (432-750,000)
CMV positive (p=NS) % 96 96
Female % 34 66
HIV+ individuals present different rate of disease progression
102 103 104 105 1060
100
200
300
400
500
600
700
800800
1200
Viral load
r=-0.57p<0.0001
200
400
18 HIV-discordant couples
Studied Pathways
c-Cytokine triggering(IL-2, IL7, IL15)
ProliferationSurvival
0 102 103 104 105
<660/20 APC OR Alexa 647-A>
0
20
40
60
80
100
0.87
0 102 103 104 105
<660/20 APC OR Alexa 647-A>
0
20
40
60
80
30.9
Phospho-Stat5
Cel
l co
un
t
No stimulation
+IL-7 (15min)
Studied T cell Subsets
Naïve and Memory subsets
Naïve CentralMemory
TransitionalMemory
EffectorMemory Effectors
proliferation
Survival
Differentiation lineage
Burgers, Riou et al. JI. 2009
Maturation
0
25
50
75
100
N CM TM EM Eff
CD8+
Ph
os
ph
o S
tat-
5 (%
)
IL-7
0
25
50
75
100
N CM TM EM Eff N CM TM EM Eff
CD8+ CD4+
IL-2
0
25
50
75
100
N CM TM EM Eff N CM TM EM Eff
CD8+ CD4+
IL-15
N CM TM EM Eff
CD4+
Ph
osp
ho
Sta
t-5
(%)
Ph
osp
ho
Sta
t-5
(%)
Cytokine responsiveness in HIV- individuals
-T cells responsiveness to cytokines decreases with Cell differentiation (CM>TM>EM>Eff) in both CD4 and CD8 compartments.
- Naïve cells are characterized by a diminished responsiveness to IL-15 and IL-2
HIV uninfected individuals
Cytokine responsiveness in HIV+ vs HIV- individuals
CD8+ cells
NHIV
pS
TA
T-5
(%
)HIV+HIV-
0
25
50
75
100
- + - + - + - + - +CM TM EM Eff
No major differences in cytokine responsiveness between HIV+ and HIV- in any CD8+ T cells subsets
IL-7
Relationship between Receptor Expression and Cell Responsiveness
- + - + - + - + - +N CM TM EM Eff
*** ***
*
CD
12
7 e
xp
res
sio
n (
%)
HIV+HIV-
IL-7 Receptor expression levels
0
25
50
75
100
0.001 0.01 0.1 10
10
20
30
40
50
Concentration IL-7 (ng/ml)IL-7 concentration (ng/ml)
pS
tat-
5 e
xp
res
sio
n (
%)
Dose response IL-7
IL-7 Receptor levels do not reflect responsiveness in HIV-infected individuals.
0 20 40 60 80 1000
10
20
30
40
50
60
70
80HIV-
HIV+
CD8 EM 127+ %
p=0.0002 (***)p=NS
IL7R expression (%)
pS
tat-
5 e
xp
res
sio
n (
%)
Correlation % IL7-R and Stat-5 response
Dissociation of Receptor expression and IL-7 responsiveness in HIV+ Individuals.
82% 64%
Total CD8+ TET+ cells
IL-7
81% 61%
Total CD8+ TET+ cells
CMV (A2-pp65) HIV (A2-Gag)
0.9%
TET-PE
SS
C
T cell responsiveness to cytokines in Antigen-specific T cells
pSTAT-5 pSTAT-5
CD8 tot CMV spe HIV spe3540455055606570758085
CD8Total
CMVspe
HIVspe
p-S
tat5
(%
)
HIV and CMV Co-infected donors with undetectable Viral Load
We can speculate that HIV-specific cells in
controllers present a Early-Differentiated
phenotype according to their high responsiveness
to IL-7.
Which HIV-specific T cells subsets associate
with viral control ?
Which HIV-specific CD8+ T cells subsets associate with viral control?
Bu
rge
rs,
Rio
u e
t al
. 20
09
0 103 104 105
<APC-A>: PHOSPHO
0
20
40
60
80
100
Viral set point at 12 months
p=0.0009r = 0.58
% Effector Memory
102 103 104 105 1060
5
10
15
20
25
30
35
40
45
Accumulation of Early differentiated cells at 6 months correlate with low viral sets point at 12 months
P-Stat-5
+IL-7
% of Central Memory
102 103 104 105 1060
3
6
9
12
15
2025303540
p=0.002r = -0.54
-HIV infection does not to alter the capacity of T cells to respond to IL-2, IL-7 and IL-15.
-T cell memory subsets show distinct phosphorylation profiles in response to exogenous cytokine stimulation: cells heading for terminal memory differentiation lose the ability to respond to IL-7.
-EM CD8+ T cells positively correlate with high viraemia
-Maintenance of CM early differentiated CD8+ T cells associates with viral control.
Conclusions
Hypothesis: early differentiated T cells capable of responding to cytokine signaling are important for controlling HIV in the
absence of ARV therapy
Potential model for Viral Control
Low Viral set point
CMEM
High responsiveness to cytokinesGood proliferation capacitiesGood survival abilities
High Viral set point
CMEM
Low responsiveness to cytokines Low proliferation capacities Low survival abilities
Desirable from a vaccine
CAPTNetworkAfrican Led,Canadian Enabled
NICD
Netty MalatsiPr. Clive Gray
Bara Clinical TeamDr. Guy de Bruyn
Pr. R.P. Sekaly
University of Montreal
PHRU, Soweto
NICD, Johannesburg
CAPTCHAVI
Funders
Recommended