Embed Size (px)
DESCRIPTION
Jacques DUTRIEUX PhD . Modified IFN- a subtypes production and chemokine networks in the thymus during acute SIV infection, impact on thymopoiesis. DUTRIEUX J. et al. , AIDS Published online march 7th 2014. Institut Cochin INSERM U1016 - PowerPoint PPT Presentation
Citation preview
www.aids2014.org
Modified IFN-a subtypes production and chemokine networks
in the thymus during acute SIV infection, impact on thymopoiesis
Jacques DUTRIEUX PhD.
DUTRIEUX J. et al., AIDS Published online march 7th 2014
Institut Cochin INSERM U1016Team « Cytokines and viral infections »
Rémi CHEYNIER
www.aids2014.org
HIV infection impacts on thymopoiesis
Thymopoiesis is rapidly affected during primary HIV infection (Hatzakis et al. 2000; Richardson et al. 2000; Douek et al. 2001; Dion et al. 2004)
Diminished thymocyte proliferation (Dion et al., 2004)
Consequence of IFN-a response ?
2
From Dion et al. 2004
Intr
a-th
ymic
pro
lifer
ation
www.aids2014.org
Acute HIV/SIV infection
3
VLIFN-a
0
10
20
30
40
50
60
0 4 8 12 2016 28100
101
102
103
104
105
106
107
108
109
Vira
l RN
A lo
ad (c
opie
s/m
l)
IFNa
(pg/
ml)
Days post-infection24
Human Rhesus macaque
In both humans and macaques :Plasma IFN-a peaks around day 10 post-infection
(Stacey et al., 2009; Khatissian et al. 1996; Giavedoni et al. 2000; Abel et al. 2002; Bruel et al., 2014, Dutrieux et al. 2014).
From Stacey et al. 2009
www.aids2014.org
Acute SIV infection study
SIVmac251 Infection (50AID50)
IV
Blood samplingD0, D3, D5, D7, D10, D12, D14
T-cell subsets analysis Thymic function
analysis
Plasma IFN-a measurement
24 rhesus macaques
Necropsy D0 (3) and in acute phase
(D3, D7, D10, D14)
Thymus sampling
IFN-a and chemokines mRNA quantifications and
identification
4
www.aids2014.org
Thymic modification in vivo
100
103
0 3 7/10 14Days post-infection
102
17 21
101
* *In
tra-
thym
ic p
rolif
erati
on
Intra-thymic proliferation decreased at day 10 post-infection
Diminished intra-thymic proliferation correlates withplasma IFN-a concentration
5
-10
0
20
30
40
50
70
Intra-thymic proliferation(Fold change)
-6 0 2-4
p=0.017r= -0.67
60
10
-2
Plas
ma
IFN
-a
www.aids2014.org
Interferon a diversity
6
From Woelk et al. 2007
13 IFNa
www.aids2014.org
IFNa
mRN
A co
pies
/ 1
03 HPR
T m
RNA
copi
es
10-1100101102103
012345678
0 3 7 10 14Days post-infection
Num
ber o
f exp
ress
ed
IFN
-a su
btyp
es
**
Thymic production of IFN-a subtypesDay 0
IFN-a1IFN-a2
IFN-a3
IFN-a4-6
IFN-a5IFN-a7IFN-a8
IFN-a9
IFN-a13
IFN-a14
IFN-a12-15
Day 3
IFN-a1IFN-a2
IFN-a3
IFN-a4-6
IFN-a5IFN-a7IFN-a8
IFN-a9
IFN-a13
IFN-a14
IFN-a12-15
Day 14
IFN-a1IFN-a2
IFN-a3
IFN-a4-6
IFN-a5IFN-a7IFN-a8
IFN-a9
IFN-a13
IFN-a14
IFN-a12-15
7
Diversified thymic IFN-a expression
www.aids2014.org
In vitro differentiation of simian thymocytes
Acidic purification
12 simian IFN-a
Simian IFN-a subtypes transfected in CHO
Flt3L
OP9-hDL1
Frequency of mature cells
Thymocyte proliferation
14 days
R-sIL-7
DN thymocytes
Healthy macaque thymus
8
www.aids2014.org
IFN-a subtypes differentially inhibit thymopoiesis
#0
20
40
60
80
100
Med
iumIFN
-a1
IFN-a
2IFN
-a3
IFN-a
4IFN
-a5
IFN-a
6IFN
-a7
IFN-a
8IFN
-a9
IFN-a
13IFN
-a14
IFN-a
12/1
5
Divi
ded
cells
(%)
Day 5Day 9Day 12
* * **
*
* **
*
IFN-a subtypes differentially inhibit thymocytes proliferation without affecting their differentiation capability
9
www.aids2014.org
IFN-a subtypes differentially inhibit thymopoiesis
#0
20
40
60
80
100
Med
iumIFN
-a1
IFN-a
2IFN
-a3
IFN-a
4IFN
-a5
IFN-a
6IFN
-a7
IFN-a
8IFN
-a9
IFN-a
13IFN
-a14
IFN-a
12/1
5
Divi
ded
cells
(%)
Day 5Day 9Day 12
In vivo-produced IFN-a subtypes demonstrate major anti-proliferative effect
10
* * **
*
* **
*
www.aids2014.org
CCL25
CXCL12
CCL19
Chemokine-driven thymocyte migrations
CCL19
11
www.aids2014.org
CCL25 transcription in the thymus
0 3 7 10 14Days post-infection
CC
L25
mR
NA
copi
es/ 1
02 HP
RT
mR
NA
copi
es
100
101
103
104
102
* *
200µm
C
C
M
C
Cortical expression Increased transcription by day 3
CCL25mRNADR
12
www.aids2014.org
CCL19 transcription in the thymus
Medullar expression Increased transcription by day 3
0 3 7 10 14Days post-infection
CC
L19
mR
NA
copi
es/ 1
02 HP
RT
mR
NA
copi
es
100
101
103
104
102
* *
200µm
C C
M
200µm
13
CCL19mRNADR
www.aids2014.org
CXCL12 transcription in the thymus
Expressed in subcapsular region Decreased transcription by day 3
CX
CL1
2 m
RN
A co
pies
/ 102 H
PR
T m
RN
A co
pies
100
101
103
104
102
105
0 3 7 10 14Days post-infection
*
200µm
C
C
M
C
C
C
CXCL12DR
14
www.aids2014.org
Diversified IFN-a production
Thymic IFN-a subtypes Inhibit thymocytes
proliferation Modified thymic chemokine network
15
CCL25
CXCL12
Proliferation
CCL19
CCL19
In the thymus
www.aids2014.org
16
CCL25
CXCL12
Proliferation
CCL19
CCL19
In the thymus
Diversified IFN-a production
Thymic IFN-a subtypes Inhibit thymocytes
proliferation Modified thymic chemokine network
Accelerated thymopoiesis
Increased thymic function
Increased naive T-cell diversity
Eventually lead to the characteristic HIV-associated thymic exhaustion
www.aids2014.org
Team Cytokines & Viral InfectionsRémi CHEYNIER
Véronique FABRE-MERSSEMANBénédicte DE MUYLDER
Suzanne MORGADOAnne COUEDEL COURTEILLEIsabelle BOURGAULT-VILADA
Magali RANCEZStéphanie BEQSandra ROZLANRosalie PONTE
Vélislava TERZIEVAAmandine BERNARDSandrine LOGEROTRaphaëlle PARKER
Primate center Institut Pasteur
Céline GOMMETXavier MONTAGUTELLI
Acknowledgements
Team Antigen presentation by dendritic cells
Agnès LEBON
Facilities
